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    08 July 2024, Volume 28 Issue 19 Previous Issue    Next Issue
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    Bone marrow mesenchymal stem cell exosomes combined with epigallocatechin-3-gallate in treatment of spinal cord ischemia/reperfusion injury in rats
    Long Zhisheng, Gong Feipeng, Wen Jiabin, Min Huan, Shu Yang, Lai Zhuoxi, Chen Gang
    2024, 28 (19):  2953-2959.  doi: 10.12307/2024.156
    Abstract ( 95 )   PDF (2116KB) ( 14 )   Save
    BACKGROUND: Studies have exhibited that inhibiting apoptosis caused by endoplasmic reticulum stress can save part of nerve function. Epigallocatechin-3-gallate can inhibit endoplasmic reticulum stress, but it has poor bioavailability and is difficult to penetrate the blood-brain barrier. In combination with exosomes targeting spinal cord repair and high-potency drug loading, theoretically, the combination of the two can play a greater role in spinal cord protection. 
    OBJECTIVE: To investigate the effects of epigallocatechin-3-gallate combined with bone marrow mesenchymal stem cell exosomes on endoplasmic reticulum stress and neurological function in rats with spinal cord ischemia/reperfusion injury. 
    METHODS: Fifty SD male rats were randomly divided into sham surgery group, model group, epigallocatechin-3-gallate group, exosome group, and combined treatment group, with 10 rats in each group. The spinal cord ischemia/reperfusion injury model was made in the other four groups except for the sham surgery group. Local injection of physiological saline, exosomes, epigallocatechin-3-gallate, epigallocatechin-3-gallate + bone marrow mesenchymal stem cell exosomes was performed 2 hours after surgery through a caudal vein. Neurological function scores were performed on 7, 14 and 28 days after spinal cord injury. 14 days after spinal cord injury, hematoxylin-eosin staining, Nissl staining, and immunofluorescence staining of endoplasmic reticulum stress markers such as ATF6 and GADD153 were performed in the spinal cord tissues. 

    RESULTS AND CONCLUSION: (1) Compared with the sham surgery group, neurological function scores of the model group, exosome group, epigallocatechin-3-gallate group and combined treatment group all decreased to different degrees. The neurological function score of combined treatment group was better than that of the epigallocatechin-3-gallate group, exosome group and model group 14 days after surgery (P < 0.05). The neurological function score of the combined treatment group was better than that of the model group and epigallocatechin-3-gallate group 28 days after surgery (P < 0.05). (2) Hematoxylin-eosin staining and Nissl staining displayed that the number of neurons in the model group decreased, with a large number of cavity necrosis and scar hyperplasia in the spinal cord injury area. The number of neurons and peripheral cavity necrosis improved to varying degrees in the epigallocatechin-3-gallate group, exosome group, and combined treatment group, with the most significant improvement in the combined treatment group. (3) The expression of endoplasmic reticulum stress-related proteins ATF6 and GADD153: 14 days postoperatively, the expression of GADD153 in the combined treatment group was lower than that in the model group and epigallocatechin-3-gallate group (P < 0.05), and the expression of ATF6 in the combined treatment group was lower than that in the model group, exosome group, and epigallocatechin-3-gallate group (P < 0.05). (4) These findings confirm that epigallocatechin-3-gallate combined with bone marrow mesenchymal stem cell exosome can enhance the neurological function in rats with spinal cord ischemia/reperfusionn injury, which may be associated with the inhibition of the expression of endoplasmic reticulum stress-related proteins ATF6 and GADD153. 

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    Shexiang Huangqi compound dripping pills-containing serum promotes proliferation and differentiation of bone marrow mesenchymal stem cells
    Chen Na, Wang Yanlin, Sun Huifang, Fan Feiyan, Li Donghong, Zhang Yunke
    2024, 28 (19):  2960-2966.  doi: 10.12307/2024.160
    Abstract ( 171 )   PDF (1583KB) ( 37 )   Save
    BACKGROUND: Bone marrow mesenchymal stem cells have been widely used to treat neurological diseases. However, due to limitations of the blood-brain barrier, low survival rate and differentiation rate of stem cells at damaged sites, the therapeutic effect is limited.
    OBJECTIVE: To investigate the effects of Shexiang Huangqi compound dripping pills on proliferation, migration and astrocyte differentiation of bone marrow mesenchymal stem cells.
    METHODS: Male SD rats were treated with Shexiang Huangqi compound dripping pills for 5 days after continuous gavage. Blood was collected from the abdominal aorta and serum was separated for later use. The effect of 5%, 10% and 20% drug-containing serum on the proliferation of bone marrow mesenchymal stem cells was detected by CCK-8 assay. The effect of 10% drug-containing serum on lateral migration of bone marrow mesenchymal stem cells was observed by scratch test. Bone marrow mesenchymal stem cells were cultured in Transwell cells. The effects of 10% drug-containing serum on longitudinal migration of bone marrow mesenchymal stem cells were observed by crystal violet staining and DAPI nuclear staining. Differentiation of bone marrow mesenchymal stem cells into astrocytes was observed by inducing solution with 10% drug-containing serum or co-culture with astrocytes. 
    RESULTS AND CONCLUSION: (1) 10% and 20% drug-containing serum promoted cell proliferation more significantly on days 2 and 3, and there was no statistical difference between the two concentrations. (2) At 30 and 48 hours, bone marrow mesenchymal stem cell migration in 10% drug-containing serum group was significantly higher than that in the control group. (3) The number of bone marrow mesenchymal stem cells filtered through Transwell cells in 10% drug-containing serum group was higher than that in the control group. (4) 10% drug-containing serum might promote the differentiation of bone marrow mesenchymal stem cells to astrocytes, but the differentiation effect was weak, and astrocytes might further promote the differentiation of bone marrow mesenchymal stem cells into astrocytes induced by drug-containing serum. (5) The results exhibited that the 10% drug-containing serum could promote the proliferation and migration of bone marrow mesenchymal stem cells in vitro. Co-culture with astrocytes may promote the differentiation of bone marrow mesenchymal stem cells towards astrocytes.
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    Regulatory effect of human umbilical cord mesenchymal stem cells on intestinal barrier function in diabetic nephropathy rats
    Wu Yaru, Mi Yan, Wei Kaiyue, Gao Heping, Zhang Dingyu, Wang Caili
    2024, 28 (19):  2967-2973.  doi: 10.12307/2024.158
    Abstract ( 151 )   PDF (2259KB) ( 20 )   Save
    BACKGROUND: Diabetic nephropathy is an important cause of end-stage renal disease, and intestinal barrier damage plays an important role in the occurrence and development of diabetic nephropathy. 
    OBJECTIVE: To observe the protective effect of human umbilical cord mesenchymal stem cells on the intestinal barrier in rats with diabetic nephropathy. 
    METHODS: Thirty 8-week-old male SD rats were randomly assigned to healthy control group, model group and human umbilical cord mesenchymal stem cell group, with 10 rats in each group. Rats in the human umbilical cord mesenchymal stem cell group were injected with 1×106 human umbilical cord mesenchymal stem cells through the tail vein once a week for 4 weeks after the model establishment of diabetic nephropathy. Rats in the healthy control group and the model group were injected with an equal volume of PBS at the same time. 1 week after the last injection, the histomorphological changes in the kidney and colon were observed under a light microscope. The expressions of ZO-1 and Occludin in the colon tissue of rats were detected by immunohistochemistry. Serum D-lactic acid and lipopolysaccharide levels were detected by ELISA. In addition, the distribution of human umbilical cord mesenchymal stem cells labeled with DiR dye in rats was observed by in vivo imaging system. The expression of human mesenchymal stem cell surface marker antigens CD44 and CD90 in colon tissue was detected by immunohistochemistry.
    RESULTS AND CONCLUSION: (1) Compared with the model group, human umbilical cord mesenchymal stem cell transplantation significantly inhibited the increase of urea nitrogen, serum creatinine, 24-hour urine protein level and urinary albumin/creatinine ratio in diabetic nephropathy rats (all P < 0.05). (2) The expression of human mesenchymal stem cell surface markers CD44 and CD90 was found in the colon of diabetic nephropathy rats. (3) Compared with the healthy control group, the expression levels of tight junction proteins Occludin and ZO-1 in the colon tissue of the model group were significantly reduced, while the expressions of Occludin and ZO-1 were significantly increased after treatment with human umbilical cord mesenchymal stem cells. (4) Compared with the model group, human umbilical cord mesenchymal stem cell transplantation significantly reduced serum D-lactic acid and lipopolysaccharide levels in diabetic nephropathy rats. (5) The results suggest that human umbilical cord mesenchymal stem cells may protect the intestinal barrier function by enhancing the expression of intestinal tight junction proteins in diabetic nephropathy rats.
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    Berberine promotes osteogenic differentiation of bone marrow mesenchymal stem cells in a high-glucose environment
    Gou Qiutong, Luo Wenhao, Wang Pin, Lan Yuyan, Liu Min, Huang Haixia
    2024, 28 (19):  2974-2980.  doi: 10.12307/2024.150
    Abstract ( 194 )   PDF (1718KB) ( 62 )   Save
    BACKGROUND: The implant osseointegration rate of patients with diabetes is low, and the failure rate is high, which seriously affects the quality of life. It is urgent to improve the implant osseointegration of patients with diabetes by effective means to elevate the success rate. Exploring the effect of berberine on the osteogenic differentiation of bone marrow mesenchymal stem cells under a high-glucose environment and its specific mechanism will provide effective theoretical support for solving the above problems.
    OBJECTIVE: To explore the effect of natural extract berberine on the osteogenic differentiation of rat bone marrow mesenchymal stem cells under the high-glucose microenvironment. 
    METHODS: Bone marrow mesenchymal stem cells of SD rats were cultured by the whole bone marrow adherence method. CCK-8 assay was used to detect the effects of different concentrations of berberine on the proliferation of bone marrow mesenchymal stem cells under the high-glucose environment and to screen out the optimal berberine concentration. The expressions of Runx2 and Osx were detected by alkaline phosphatase activity, alicarin red staining and PCR to determine the effect of berberine on osteogenic differentiation of bone marrow mesymal stem cells under the high-glucose environment. To further explore the underlying mechanism, we introduced the AMPK-specific inhibitor Dorsomorphin and used a DCFH-DA reactive oxygen species fluorescent probe to examine reactive oxygen species levels. The p-AMPK expression was also determined by western blot assay.
    RESULTS AND CONCLUSION: (1) 10 µmol/L was the optimal concentration of berberine to promote bone marrow mesenchymal stem cell proliferation. (2) Alberberine promoted alkaline phosphatase viability of bone marrow mesenchymal stem cells and mineralized nodule formation in a high-glucose microenvironment. (3) Alberberine promoted the expression of Runx2 and OSx in a high-glucose microenvironment. (4) Alberensine effectively inhibited the reactive oxygen species level of bone marrow mesenchymal stem cells in a high-glucose environment. (5) The effects of berberine on promoting bone marrow mesenchymal stem cell osteogenesis and inhibition of reactive oxygen species were reversed by the AMPK inhibitor. (6) Berberine activated AMPK and promoted p-AMPK expression. (7) The above results indicate that berberine (10 µmol/L) promotes the osteogenic differentiation of bone marrow mesenchymal stem cells in a high-glucose environment by activating AMPK and reducing intracellular reactive oxygen species levels. 
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    Vitamin D3 attenuates high-glucose exposure-induced oxidative stress to promote osteogenic differentiation of human umbilical cord mesenchymal stem cells
    Xie Ting, Liu Tingting, Zeng Xuehui, Li Yamin, Zhou Panghu, Yi Nianhua
    2024, 28 (19):  2981-2987.  doi: 10.12307/2024.179
    Abstract ( 80 )   PDF (1879KB) ( 20 )   Save
    BACKGROUND: Diabetic osteoporosis is gaining public attention. However, few studies have reported the effect of a high-glucose environment on the osteogenic differentiation of human umbilical cord mesenchymal stem cells and the corresponding therapeutic strategies.
    OBJECTIVE: To investigate whether vitamin D3 can restore the osteogenic differentiation potential of human umbilical cord mesenchymal stem cells in a high-glucose environment. 
    METHODS: The viability of human umbilical cord mesenchymal stem cells was detected by CCK-8 assay to screen the appropriate vitamin D3 intervention concentration. Under the high-glucose environment, RT-qPCR, western blot assay, immunofluorescence, JC-1 mitochondrial membrane potential, alizarin red staining, and β-galactosidase staining were used to evaluate the osteogenic differentiation potential, intracellular reactive oxygen species accumulation, mitochondrial membrane potential alteration, and cell senescence of human umbilical cord mesenchymal stem cells after vitamin D3 intervention. The underlying mechanism was also discussed.
    RESULTS AND CONCLUSION: (1) Vitamin D3 significantly promoted the proliferation of human umbilical cord mesenchymal stem cells in the range of 0.1 μmol/L to 1 mmol/L. (2) High-glucose environment down-regulated the mRNA and protein level expressions of osteogenic-related genes α1-I collagen, alkaline phosphatase, Runt-associated transcription factor 2, and osteocalcin in human umbilical cord mesenchymal stem cells, which induced oxidative stress and cellular senescence. (3) Vitamin D3 at an intervention concentration of 10 μmol/L significantly restored the osteogenic phenotype of human umbilical cord mesenchymal stem cells under high-glucose conditions and attenuated intracellular oxidative stress and cellular senescence by activating the Nrf2/HO-1 signaling pathway. (4) These findings suggested that the osteogenic differentiation ability of human umbilical cord mesenchymal stem cells was reduced in the high-glucose environment, and vitamin D3 could partially improve their osteogenic differentiation ability and reduce cell damage.
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    Adipose-derived mesenchymal stem cell-derived exosomes alleviate hydrogen peroxide-induced PC12 cell apoptosis
    Gu Chengxu, Zhang Naili, Meng Yongchun, Liu Qing, Guo Qixuan, Fu Li, Zhang Luping, Huang Fei
    2024, 28 (19):  2988-2995.  doi: 10.12307/2024.165
    Abstract ( 172 )   PDF (1475KB) ( 61 )   Save
    BACKGROUND: Mesenchymal stem cell-derived exosomes may play a crucial role in tissue damage repair, and miRNA is an important component of exosomes for therapeutic effects. Among them, miR-29b-3p has the effect of reducing cell apoptosis, promoting axonal regeneration, and angiogenesis.
    OBJECTIVE: To study the protective effect of adipose-derived mesenchymal stem cell-derived exosome via miR-29b-3p on a neural cell injury model simulated by H2O2-treated PC12 cells, and explore the relevant mechanisms.
    METHODS: (1) First, the collagenase digestion method was used to extract rat adipose-derived mesenchymal stem cells. Adipose-derived mesenchymal stem cells were transfected with miR-29b-3p mimics and inhibitors. Exosomes were extracted from the culture supernatant by ultracentrifugation and identified so as to construct adipose-derived mesenchymal stem cell-derived exosomes with high expression and knockdown miR-29b-3p. (2) By constructing a neural cell injury model simulated by PC12 cells treated with H2O2, the relevant mechanisms of the protective effect of adipose-derived mesenchymal stem cell-derived exosome via miR-29b-3p on the simulated neuronal cell injury model were studied.
    RESULTS AND CONCLUSION: (1) Adipose-derived mesenchymal stem cell-derived exosome had a typical cup-shaped shape and a diameter distribution in the range of 50-140 nm, expressed membrane proteins Alix, CD63, and TSG101, which were specific markers on the surface of exosomes, and could be successfully ingested by PC12 cells. (2) Adipose-derived mesenchymal stem cell-derived exosome pretreatment could reduce cell apoptosis induced by H2O2 treatment in PC12 cells, and this protective effect was enhanced with the increase of miR-29b-3p expression in the exosomes and weakened with the decrease of miR-29b-3p expression in the exosomes. The mechanism of its effect was related to adipose-derived mesenchymal stem cell-derived exosome via miR-29b-3p promoting the expression of anti-apoptotic protein Bcl-2 and inhibiting the expression of apoptotic protein Bax.
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    Effects of aging factors on biological characteristics of dental stem cells
    Xu Zhiguo, Wu Yanfei, Ren Zhenhui, Yang Xuwei, Niu Yikun, Dong Zhilong, Du Wei, Yang Wenling, Xu Xin, Zhu Yi, Liu Lefeng, Liu Chao
    2024, 28 (19):  2996-3002.  doi: 10.12307/2024.159
    Abstract ( 171 )   PDF (2636KB) ( 56 )   Save
    BACKGROUND: The research of dental stem cells in the fields of regenerative medicine and tissue engineering has been deepening, bringing hope for the repair of tooth-related tissues and the treatment of systemic diseases. However, there is a lack of systematic research and analysis on the biological characteristics of dental stem cells in different age groups. 
    OBJECTIVE: To explore the biological characteristics of the human deciduous tooth and permanent tooth pulp stem cells cultured in umbilical cord blood platelet lysate to provide a reliable basis for human platelet lysates to replace fetal bovine serum.  
    METHODS: The pulp tissues of deciduous teeth, juvenile permanent teeth and adult permanent teeth were taken out and cultured in DMEM/F-12 medium supplemented with 10% fetal bovine serum or different concentrations (5%, 10% and 15%) of human platelet lysates. Cell proliferation in the four groups was detected by cytometry. The optimal concentration of human platelet lysates was selected for subsequent experiments. Under the optimal concentration of human platelet lysates, human deciduous tooth and juvenile and adult permanent tooth pulp stem cells were cultured in vitro. The cell growth status was observed under the microscope. The specific antigen on the cell surface was detected by flow cytometry. The cell proliferation ability was tested by the cell counting method and CCK-8 assay. The cell differentiation ability in vitro was observed by a three-line differentiation assay.
    RESULTS AND CONCLUSION: (1) The cell proliferation rate of the 10% human platelet lysate group was the highest. (2) In all three groups, fusiform fibrous cells grew and expanded from around the tissue block. There was no significant difference between deciduous teeth and juvenile permanent tooth cells, but the adult permanent tooth cells were larger than the deciduous and juvenile permanent tooth cells of the same generation. (3) The results of flow cytometry showed that deciduous teeth, juvenile permanent teeth and adult permanent teeth conformed to the phenotypic characteristics of mesenchymal stem cells. (4) The proliferative capacity of adult permanent dental pulp stem cells was significantly lower than those of deciduous teeth and juvenile permanent dental pulp stem cells (P < 0.01). (5) mRNA expressions of osteoblast-related genes alkaline phosphatase and bone morphogenetic protein 2, lipoprotein lipase and peroxisome proliferator-activated receptor γ2, mRNA expressions of chondroblast related gene type II collagen α1 and cartilage oligomeric matrix protein in adult pulp stem cells of permanent teeth were significantly lower than those of deciduous teeth and juvenile permanent teeth pulp stem cells (P < 0.01). (6) Compared with adult dental pulp stem cells, human deciduous teeth and juvenile permanent teeth dental pulp stem cells have the stronger proliferative capacity and multidirectional differentiation potential, and are more suitable for clinical research and disease treatment.
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    miR-135a-5p regulates autophagy of mouse embryonic palatal mesenchymal cells via targeting Kif3B
    Feng Wenxuan, Lian Shubo, Wang Zhe, Chen Jing, He Wei
    2024, 28 (19):  3003-3011.  doi: 10.12307/2024.151
    Abstract ( 156 )   PDF (1998KB) ( 9 )   Save
    BACKGROUND: Studies demonstrated that miR-135a-5p was highly expressed in mouse embryonic palatal mesenchymal cells with cleft palate induced by dexamethasone. The primary cilium and its mediated Shh signaling pathway were involved in the autophagy of mouse embryonic palatal mesenchymal cells. It is speculated that miR-135a-5p may regulate autophagy in mouse embryonic palatal mesenchymal cells through primary cilia and its mediated Shh signaling pathway.
    OBJECTIVE: To investigate the regulatory effect of miR-135a-5p on autophagy of mouse embryonic palatal mesenchymal cells.
    METHODS: In vitro, palatal mesenchymal cells from C57BL/6J mouse embryos were extracted and cultured. Cell transfections were set up as follows: (1) the cells were divided into control group, miR-135a-5p negative control group and miR-135a-5p mimic group; (2) NC+miR-NC group, KIF3B overexpression group, and miR-135a-5p+KIF3B group: qRT-PCR was performed to verify transfection efficiency of miR-135a-5p and KIF3B. A transmission electron microscope was used to observe the number of autophagosome/autophagolysosome in the cells of each group. The degree of fluorescence expression of autophagy marker LC3B was determined by the immunofluorescence technique. The protein expression of KIF3B, LC3 and P62 was determined by western blot assay. (3) The cells were divided into miR-135a-5p negative control group, and SAG treated group, and SAG+miR-135a-5p group. qRT-PCR was used to detect the mRNA expression levels of Gli3, a key transcription factor downstream of Shh signaling. The protein expressions of autophagy-related proteins LC3 and P62 were detected by western blot assay. 
    RESULTS AND CONCLUSION: (1) After overexpression of miR-135a-5p, the number of autophagosome/autophagolysosome was significantly increased (P < 0.01). The fluorescence density of LC3B increased significantly (P < 0.01); the protein expression of KIF3B and P62 decreased (P < 0.01), and the protein expression of LC3 increased. (2) After overexpression of KIF3B, the number of autophagosome/autophagolysosome was significantly decreased (P < 0.01); the fluorescence density of LC3B was decreased (P < 0.01); the protein expression of P62 was increased (P < 0.01), and the protein expression of LC3 was decreased (P < 0.01). Targeted expression of KIF3B was inhibited by miR-135a-5p (P < 0.01); the number of autophagosome/autophagolysosome, the fluorescence intensity of LC3B as well as the protein expression of LC3 were reversed (P < 0.01) and the protein expression of P62 was decreased (P < 0.01). (3) SAG significantly increased the mRNA expression of Gli3 (P < 0.01), increased the protein expression of P62 (P < 0.01), and decreased the protein expression of LC3 (P < 0.01). When miR-135a-5p was added, Gli3 mRNA expression was significantly decreased (P < 0.01); P62 protein expression was decreased (P < 0.01), and LC3 protein expression was reversed (P < 0.01). (4) These results indicate that miR-135a-5p targets the inhibition of KIF3B and promotes autophagy in mouse embryonic mesenchymal cells possibly by negatively regulating the Shh signaling pathway.
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    Effects of spheroid culture in a rotating bioreactor on secretion of inflammatory factors by human placenta-derived mesenchymal stem cells
    Zhang Pingping, Liang Tingting, Fan Mingsong, Chen Li, Zhang Shichang
    2024, 28 (19):  3012-3017.  doi: 10.12307/2024.177
    Abstract ( 204 )   PDF (1181KB) ( 85 )   Save

    BACKGROUND: Spheroid culture of mesenchymal stem cells in bioreactors is an in vitro culture method to maintain their stemness properties and allow for large-scale expansion. Clarifying its effects on the immunoregulation effect of stem cells is beneficial for their clinical application.

    OBJECTIVE: To investigate the effects of spheroid culture in a rotating bioreactor on the secretion of inflammatory factors by human placenta-derived mesenchymal stem cells.
    METHODS: Placenta-derived mesenchymal stem cells isolated from human placenta tissue were cultured in two-dimensional culture or a rotating bioreactor culture. Cell morphology and proliferation ability were observed using inverted phase contrast microscopy, immunohistochemical staining, and CCK-8 assay. The gene expression and protein secretion of several inflammatory factors were detected by RT-qPCR and flow immunofluorescence assay.
    RESULTS AND CONCLUSION: (1) Mesenchymal stem cells cultured in a rotating bioreactor aggregated into multicellular spheroids, which gradually increased in number and volume. (2) The hematoxylin-eosin staining results showed that the mesenchymal stem cells cultured in the rotating bioreactor for 4 days were evenly distributed and had normal morphology in the spheroids. (3) Immunohistochemical staining results revealed many mesenchymal stem cells with Ki-67 positive in the spheroids. (4) The CCK-8 assay results exhibited that the viability of mesenchymal stem cells derived from spheroid culture was significantly higher than that of cells cultured in two-dimensional culture. (5) The results of RT-qPCR and flow immunofluorescence assay demonstrated that the gene expression and protein secretion (interleukin 1β, interleukin-4, interleukin-6, interleukin-8, interleukin-10, interleukin-17, tumor necrosis factor α and interferon α) of inflammatory factors derived from mesenchymal stem cells cultured in the rotating bioreactor were significantly higher than those in two-dimensional culture. (6) Our results indicate that spheroid culture in a rotating bioreactor can significantly elevate the secretion ability of various inflammatory factors by human placenta-derived mesenchymal stem cells, and enhance the immunoregulatory effect of human placenta-derived mesenchymal stem cells. 

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    Effects of repeated superovulation on developmental potential of oocytes in mice and humans
    Li Chong, Shen Xiaoli, Yang Jingwei, Guo Jing, Xie Juan, Huang Guoning, Li Jingyu
    2024, 28 (19):  3018-3023.  doi: 10.12307/2024.125
    Abstract ( 178 )   PDF (1556KB) ( 17 )   Save
    BACKGROUND: Superovulation is a common therapy in assisted reproductive technology. In clinical practice, some patients experience repeated superovulation to get pregnant.
    OBJECTIVE: To explore the effect of repeated superovulation on the developmental potential of oocytes in mice and humans.  
    METHODS: Both animal experiments and retrospective clinical research were conducted. The animal study involved 90 SPF grade ICR 8-week-old female mice, who were randomly divided into three groups for 1, 3, and 5 superovulations, respectively. The clinical study involved 306 patients who had undergone three consecutive in vitro fertilization cycles. The number of ovules obtained and embryonic development in different cycles were compared. 
    RESULTS AND CONCLUSION: (1) The animal study indicated that repeated superovulation did not affect the embryonic development or developmental speed of mouse embryos. Similarly, there was no significant difference in the mouse blastocyst apoptosis, DNA damage, or the formation of inner cell mass and trophectoderm (P > 0.05). (2) The clinical study also revealed no significant differences in the number of retrieved oocytes (8.60±5.04, 8.58±4.87, and 8.38±4.63, P=0.81) and transferable embryos (2.42±1.99, 2.40±1.92, and 2.64±2.00, P=0.26) over the three cycles. (3) In both the young group (< 35 years) and the old group (≥ 35 years), the embryo quality was not affected by repeated superovulation (P > 0.05). (4) These findings show that repeated superovulation does not affect the developmental potential of oocytes in mice and humans. 
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    Differential effects of hypoxia and oxidative stress on paracrine of mesenchymal stem cells from different sources
    Pan Xiaoying, Xu Yongde, Liu Zhiqiang, Xing Xiaowen, Yang Yong
    2024, 28 (19):  3024-3030.  doi: 10.12307/2024.140
    Abstract ( 178 )   PDF (1288KB) ( 18 )   Save
    BACKGROUND: The biological behavior of mesenchymal stem cells is influenced by the survival microenvironment. Pre-treatment of the microenvironment is an important means of regulating the function of mesenchymal stem cells. 
    OBJECTIVE: To compare the differences in paracrine function of umbilical cord mesenchymal stem cells and adipose mesenchymal stem cells under oxidative stress and hypoxia, and to provide a theoretical basis for selecting appropriate pretreatment of mesenchymal stem cells to treat different diseases.
    METHODS: Umbilical cord mesenchymal stem cells and adipose mesenchymal stem cells were cultured by H2O2 or O2 oxygen, respectively, and cell morphology, proliferation, viability and paracrine factor expression were examined.
    RESULTS AND CONCLUSION: (1) The expression levels of brain-derived neurotrophic factor and transforming growth factor-β were higher in umbilical cord mesenchymal stem cells than in adipose mesenchymal stem cells under a normal culture environment, while the expressions of stromal cell-derived factor-1α and tumor necrosis factor stimulating factor-6 in the adipose mesenchymal stem cells were significantly higher than those in the umbilical cord mesenchymal stem cells. (2) There was no significant difference in the effect of low and moderate levels (≤ 100 μmol/L) of H2O2 on the viability of the two mesenchymal stem cells. However, increasing the H2O2 concentration from 50 μmol/L to 100 μmol/L resulted in a distinct increase in vascular endothelial growth factor expression in umbilical cord mesenchymal stem cells. The expression of basic fibroblast growth factor, vascular endothelial growth factor, stromal cell-derived factor-1α and interleukin-10 in adipose mesenchymal stem cells was greatly increased by increasing H2O2 concentration in this range. (3) 1% O2 hypoxia promoted mesenchymal stem cell proliferation. After 24 hours of culture in 1% O2, gene expression levels were elevated in both mesenchymal stem cells, but the expression levels of vascular endothelial growth factor, interleukin-10 and tumor necrosis factor stimulating factor-6 were significantly higher in adipose mesenchymal stem cells than in umbilical cord mesenchymal stem cells. (4) It is concluded that hypoxia and oxidative stress preconditioning enhances the paracrine function of mesenchymal stem cells. However, mesenchymal stem cells respond differently to hypoxia and oxidative stress. Treating diseases can choose suitable mesenchymal stem cells for appropriate pretreatment to further enhance their therapeutic potential.
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    Effects and mechanisms of calycosin on endothelial differentiation of human induced pluripotent stem cells
    Cui Shengnan, Liu Chuanguo, Yang Wenqing, Zheng Zhijuan, Zhang Dan
    2024, 28 (19):  3031-3036.  doi: 10.12307/2024.167
    Abstract ( 169 )   PDF (1298KB) ( 56 )   Save
    BACKGROUND: Endothelial injury is one of the causes of cardiovascular diseases. Human induced pluripotent stem cells are easy to obtain, have strong differentiation ability, and have less exclusiveness, and their endothelial differentiated cells can be used as ideal cells for cardiovascular disease research.
    OBJECTIVE: To investigate the effect and mechanism of calycosin on endothelial differentiation of human induced pluripotent stem cells and to provide technical support for microvascular regeneration.
    METHODS: Human induced pluripotent stem cells were divided into control group and calycosin group (1.25, 2.5 μg/mL), and growth factors were added to induce single-layer endothelial differentiation. After the induction of differentiation for 8 days, the positive rate of endothelial cell marker CD144 was detected by flow cytometry. Fluorescent expressions of CD144 and CD31 were detected by the immunofluorescence method. Lentivirus RNAi GFP puromycin was used to silence human-induced pluripotent stem cell Piezo1 mRNA followed by endothelial directed differentiation. After 8 days of differentiation, the positive rate of CD144 in differentiated cells was detected by flow cytometry. The mRNA expression levels of CD144, Piezo1 and MEK were detected by qPCR. 
    RESULTS AND CONCLUSION: (1) Compared with the control group, the positive rate of CD144 was significantly increased in the 1.25 and 2.5 μg/mL calycosin groups (P < 0.05). The expressions of CD144, Piezo1, and MEK mRNA were increased in the 2.5 μg/mL calycosin group (P < 0.05). The fluorescence expressions of CD144 (P < 0.01) and CD31 (P < 0.001) were significantly increased in the 2.5 μg/mL calycosin group. (2) Compared with the shNT group, CD144 positive rate and CD144, Piezo1, MEK mRNA expressions were significantly increased in the shNT + calycosin 1.25, 2.5 μg/mL groups (P < 0.05). Compared with the shPiezo1 group, the positive rate of CD144 and mRNA expressions of CD144, Piezo1 and MEK had no significant changes in the shPiezo1+calycosin 1.25, 2.5 μg/mL groups (P > 0.05). (3) It is concluded that 2.5 μg/mL calycosin promotes the differentiation of human-induced pluripotent stem cells into endothelial lineages. Calycosin promotes the downstream MEK expression, thereby promoting the endothelial differentiation of human induced pluripotent stem cells by targeting the expression level of Piezo1. 
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    Effect of Zishen-Yutai pills on refrozen-thawed embryo transfer in patients with diminished ovarian reserve
    Zhang Jinghua, Bai Lijing, Yu Chunmei
    2024, 28 (19):  3037-3041.  doi: 10.12307/2024.129
    Abstract ( 184 )   PDF (917KB) ( 45 )   Save
    BACKGROUND: Currently, hormone replacement therapy is the main treatment in Western medicine for patients with decreased ovarian function, but these patients are not sensitive to exogenous hormones, leading to unsatisfactory therapeutic effect. Zishen-Yutai pills can nourish the blood and calm the fetus, tonify the kidney and spleen, invigorate qi and strengthen the body. Studies have confirmed that Zishen-Yutai pill is effective in reducing follicle-stimulating hormone index and improving traditional Chinese medicine symptoms in patients with diminished ovarian reserve. However, few studies have been conducted to improve the implantation rate of patients by improving endometrial receptivity. 
    OBJECTIVE: To evaluate the effect of Zishen-Yutai pills on the clinical outcome of patients with diminished ovarian reserve undergoing frozen-thawed embryo transfer again.  
    METHODS:  A total of 300 patients with diminished ovarian reserve who underwent frozen-thawed embryo transfer to assist pregnancy after the first failure in the Center of Reproductive Medicine, Changzhou Maternal and Child Health Care Hospital from January 2019 to December 2021 were selected as the study subjects. Subjects were randomly treated with a placebo or Zishen-Yutai pills in a ratio of 1:2, with 100 cases in the treatment group and 200 cases in the control group. However, 13 patients fell off due to lack of contact, refusal to take medicine or other reasons. Finally, 90 cases in the treatment group and 197 cases in the control group were included in the study. Oral medication was administered 7 days before frozen-thawed embryo transfer transplantation at a dose of 5 g/time, 3 times/day. To investigate whether taking Zishen-Yutai pills could improve the clinical outcome of patients with diminished ovarian reserve after frozen-thawed embryo transfer again, the primary outcome measures included clinical pregnancy rate, implantation rate, abortion rate, live birth rate, offspring birth weight and birth defects.
    RESULTS AND CONCLUSION: Compared with the control group, the clinical pregnancy rate (P < 0.05) and implantation rate (P=0.009) were significantly increased after the oral administration of Zishen-Yutai pills. Correlation analysis showed that taking the Zishen-Yutai pill was positively correlated with the number of implanted embryos (r=0.200, P=0.001) and clinical pregnancy (r=0.235, P=0.000). There was no correlation between taking Zishen-Yutai pills and indexes of endometrial thickness and blood flow. It is indicated that Zishen-Yutai pills can improve the clinical pregnancy rate and implantation rate of frozen-thawed embryo transfer recurrence in patients with diminished ovarian reserve.
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    Expression pattern and signification of Cx43, beta-catenin and Smo in the second heart field
    Ding Zeyuan, Yan Yunan, Xie Jianshan, Shi Liang, Jing Ya, Yang Yanping
    2024, 28 (19):  3042-3048.  doi: 10.12307/2024.143
    Abstract ( 148 )   PDF (2357KB) ( 13 )   Save
    BACKGROUND: The second heart field is crucial for the development of the embryonic heart. Abnormal development of the second heart field can result in multiple cardiac malformations. After Cx43 gene knockout, reduced formation and proliferation of cells of the second heart field can be observed, but the specific reason remains unclear.  
    OBJECTIVE: (1) To determine whether β-catenin, Smo and Cx43 were co-expressed in the second heart field and the endoderm, we observed the expression patterns of these proteins. (2) To explore whether Cx43 interacts with the Wnt/β-catenin pathway or the Shh pathway in the development of the second heart field.
    METHODS: Serial paraffin sections of the mouse embryos at embryonic days 10-12 were selected for immunohistochemical staining, hematoxylin-eosin staining and immunofluorescence staining. The primitive gut of mouse embryos at embryonic day 11 was separated for western blot assay and co-immunoprecipitation.
    RESULTS AND CONCLUSION: (1) Cx43 and Isl1 were co-expressed in some mesenchymal cells on the ventral side of the foregut and dorsal wall of the pericardial cavity of mouse embryos at embryonic days 10-12; Isl1 positive cells increased while Cx43 positive cells increased. (2) Cx43 and β-catenin were co-expressed in the ventral part of the endoderm at embryonic days 10-12. (3) Cx43 and Smo were co-expressed in the endoderm at embryonic days 10-12. (4) The co-immunoprecipitation results confirmed that there was an interaction between Cx43 and β-catenin, which suggested that Cx43 interacted with β-catenin to participate in the development of the second heart field.
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    Expression and action mechanism of stromal cell-derived factor 1 in tendon-bone healing of rabbit rotator cuff
    Wang Xu, Wu Yajie, Zhang Xinfu, Shi Zhi, Yang Tengyun, Xiong Bohan, Lu Xiaojun, Zhao Daohong
    2024, 28 (19):  3049-3054.  doi: 10.12307/2024.157
    Abstract ( 149 )   PDF (2056KB) ( 43 )   Save
    BACKGROUND: In recent years, some scholars in the field of tendon bone injury have attached stromal cell-derived factor 1 to tissue engineering scaffolds to promote tendon bone healing, and achieved good results. However, whether stromal cell-derived factor 1 promotes tendon bone healing mechanisms and participates in the repair of natural healing has not yet been defined. 
    OBJECTIVE: To study the expression of stroma-cell derived factor 1 during tendon bone healing after rupture of the whole supraspinatus muscle of the rabbit rotator cuff and its migration effect and optimal in vitro migration promoting concentration on stem cells during tendon bone injury.
    METHODS: Totally 18 adult New Zealand rabbits were randomly selected to establish rotator cuff injury models, and an additional 3 rabbits were selected as blank controls. At 3, 5, 7, 14, 21, and 28 days after modeling, three rabbits were executed separately and the rabbits in the blank group were sacrificed. The tissues of tendon bone junction were taken and stored in a -80 ℃ refrigerator. The expression of stromal cell-derived factor 1 was detected by ELISA at each time point after injury. Mesenchymal stem cells were isolated from the bone marrow of young rabbit femur, cultured, and identified. Transwell assay was performed to verify the migration-promoting effect of stromal cell-derived factor 1 on stem cells and the optimal migration-promoting concentration in vitro. The stem cells cultured to P3 were co-cultured with BrdU and injected into the rabbit ear marginal vein, and immunohistochemical staining was used to verify whether the stem cells migrated to the injury site. 
    RESULTS AND CONCLUSION: (1) Stromal cell-derived factor 1 gene expression was bimodal during rotator cuff tendon bone healing. Stromal cell-derived factor 1 gene expression increased significantly at 3 days post-injury (P < 0.01) and then decreased, reaching a minimum at 5 days post-injury. It increased again and reached a peak 14 days after injury (P < 0.01) and then decreased. (2) Cell immunohistochemical staining displayed that stem cells labeled with BrdU did migrate to the injury site. (3) The results of the transwell experiment exhibited that 60-80 ng/mL stromal cell-derived factor 1 had the best effect on promoting migration of stem cells, while a concentration of 200 ng/mL inhibited migration. (4) Stromal cell-derived factor 1 is involved in the healing of rotator cuff tendon bone during the inflammatory response phase and the proliferation phase. The mechanism of action may be to promote the migration of stem cells to the injury and their differentiation into various types of cells to promote repair. In addition, the pro-migration effect of stromal cell-derived factor 1 exists at a range of concentrations, beyond which it may act as an inhibitor.
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    Oxidized high-density lipoprotein promotes rat ovarian granulosa cell apoptosis through reactive oxygen species-initiated p38 signaling pathway
    Guo Qin, Wu Minmin, Tao Ying
    2024, 28 (19):  3055-3060.  doi: 10.12307/2024.168
    Abstract ( 148 )   PDF (1685KB) ( 9 )   Save
    BACKGROUND: Oxidative modification of high-density lipoprotein occurs in patients with polycystic ovary syndrome. However, the relationship between oxidized high-density lipoprotein and ovulation dysfunction and its mechanism are unknown. 
    OBJECTIVE: To investigate the effect and potential mechanism of oxidized high-density lipoprotein on ovarian granulosa cell apoptosis.  
    METHODS: Polycystic ovary syndrome rat model was established, then the high-density lipoprotein was harvested from the rat serum of heart blood. The degree of oxidation of the high-density lipoprotein was detected by high-density lipoprotein inflammation index assay, malondialdehyde assay and lipoprotein agarose gel electrophoresis assay. The normal rat ovarian granulosa cells were isolated and treated with high-density lipoprotein and oxidized high-density lipoprotein isolated from the model rat serum. Cell viability was detected by CCK-8 assay. Cell apoptosis was detected by flow cytometry. The generation of reactive oxygen species was detected by H2DCF-DA staining. The p38 signaling activity was detected by western blot assay. Ovarian granulosa cells were pretreated with reactive oxygen species inhibitors N-acetylcysteine, tetramethylpiperidine (Tempol) and p38 inhibitor SB203580, and then treated with oxidized high-density lipoprotein. Finally, cell apoptosis, reactive oxygen species production and p38 signaling activity were detected. 
    RESULTS AND CONCLUSION: A portion of the high-density lipoprotein from the serum of polycystic ovary syndrome model rats affected oxidative modification. High-density lipoprotein and oxidized high-density lipoprotein isolated from the model rat serum inhibited granulosa cell viability and promoted apoptosis (all P < 0.05). They promoted rat granulosa cell reactive oxygen species production and p38 activation (all P < 0.05). N-acetylcysteine, Tempol and SB203580 reversed oxidized high-density lipoprotein induced granulosa cell apoptosis (all P < 0.05). N-acetylcysteine and Tempol suppressed oxidized high-density lipoprotein-induced p38 activation (all P < 0.05). SB203580 did not have a regulatory effect on reactive oxygen species production (P > 0.05). In summary, polycystic ovary syndrome can promote partial oxidative modification of high-density lipoprotein. The oxidized high-density lipoprotein promotes rat granulosa cell apoptosis by the activation of the reactive oxygen species-initiated p38 signaling pathway. 
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    Construction and validation of pregnancy prediction model of artificial insemination by husband based on endometrial structure and uterine spiral artery blood flow parameters
    Yu Guangyu, Fan Jiaqi, Chen Shibei, Gao Leilei, Yu Qing, Zhou Chao, Yu Chunmei, Jin Zhen
    2024, 28 (19):  3061-3068.  doi: 10.12307/2024.162
    Abstract ( 168 )   PDF (1125KB) ( 44 )   Save
    BACKGROUND: The impact of the endometrium’s structure and spiral artery blood flow parameters on the pregnancy rate of artificial insemination by husband remains unclear. This study identified the independent factors and constructed a prediction model with good clinical application efficacy after calibration of other confounding factors.
    OBJECTIVE: To construct and validate a clinical pregnancy prediction model for artificial insemination by husband based on endometrial structure and uterine spiral artery blood flow parameters. 
    METHODS: A retrospective analysis was conducted on 1 299 patients who underwent artificial insemination by husband treatment at Changzhou Maternal and Child Health Hospital from January 2017 to January 2021. The non-pregnancy group consisted of 1 182 patients, while the pregnancy group included 117 patients. Out of these patients, 93 cases were successfully matched between the pregnancy and non-pregnancy groups using a 1:1 propensity score matching method. Single-factor and multi-factor analyses were used to screen the endometrial structure and uterine spiral artery blood flow parameters to determine their influence on artificial insemination by husband outcomes. The optimal cutoff value was established for each independent influencing factor through receiver operating curve analysis and their risk trend affecting artificial insemination by husband pregnancy outcomes was analyzed using a restricted cubic spline. The clinical efficacy of this combined forecast model was tested by using clinical decision curve and clinical influence curve methods.
    RESULTS AND CONCLUSION: (1) There was no statistical significance in non-endometrial factors between the pregnancy group and the non-pregnancy group, and the data had a good balance by propensity score matching (P > 0.05). (2) Single-factor analysis identified several subendometrial parameters as significant influencing factors of artificial insemination by husband pregnancy outcomes, including vascularization index, flow index, vascular flow index, resistance index, pulsatility index, maximum systolic velocity/end-diastolic velocity, thickness of average junction zone and maximum junction zone from the basal endometrium to the outer myometrium inner layer (P < 0.05). (3) Multivariate logistic regression analysis revealed that thickness of average junction zone, pulsatility index, and vascular flow index were independent influencing factors of pregnancy outcomes of artificial insemination by husband, vascular flow index > thickness of average junction zone > pulsatility index. (4) Receiver operating characteristic curve analysis indicated that the area under receiver operating characteristic curve of vascular flow index was 0.704 (0.629, 0.779), and the optimal cutoff value was 6.26; the area under receiver operating characteristic curve of thickness of average junction zone was 0.660 (0.582, 0.739), and the optimal cutoff value was 6.38; the area under receiver operating characteristic curve of pulsatility index was 0.642 (0.563, 0.721), and the optimal cutoff value was 1.18. (5) The restricted cubic spline analysis revealed that artificial insemination by husband pregnancy outcomes were significantly positively affected when the vascular flow index was > 6.24 or the thickness of average junction zone was ≤6.55 mm, while a negative risk was associated with pulsatility index > 1.27. (6) The clinical decision curve and clinical influence curve analyses exhibited that the combined prediction model had the maximum clinical net benefit at the threshold probability value of 0.17-0.93, and the ratio of loss to benefit was consistently less than 1 in the threshold probability range, indicating that the model had good clinical efficacy. (7) It is concluded that after adjusting for other confounding factors outside of the endometrium using propensity score matching and multifactorial logistic regression, the thickness of average junction zone, pulsatility index and vascular flow index were independent factors that influenced pregnancy outcomes of artificial insemination by husband. Through determining their optimal cutoff values and assessing their risk trends, it was confirmed that the combined prediction model had good predictive value and clinical efficacy. 
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    Photobiomodulation-induced osteogenic differentiation of mesenchymal stem cells
    Song Yue, Shu Qing, Jia Shaohui, Tian Jun
    2024, 28 (19):  3069-3075.  doi: 10.12307/2024.163
    Abstract ( 170 )   PDF (1118KB) ( 26 )   Save
    BACKGROUND: Mesenchymal stem cells are pluripotent stromal cells isolated from a variety of tissues, which can differentiate into osteoblasts under certain conditions. Photobiomodulation, as an external stimulus, can promote osteogenic differentiation combined with other inducers or alone, providing new ideas for solving a series of bone diseases.
    OBJECTIVE: To review the relevant literature and mechanisms of photobiomodulation-induced osteogenic differentiation of mesenchymal stem cells, which will lay a theoretical foundation for bone tissue engineering using mesenchymal stem cells as seed cells and may offer some suggestions for future studies.
    METHODS: Relevant articles were searched on CNKI, PubMed and Wed of Science databases with Chinese search terms of “photobiomodulation, low power laser, low level laser, light-emitting diode, mesenchymal stem cells, osteogenic differentiation, biomaterials” and English search terms of “photobiomodulation, low level laser (light), light-emitting diode (LED), mesenchymal stem cell, osteogenic differentiation, biomaterials”. Finally, 88 articles were included for analysis.
    RESULTS AND CONCLUSION: (1) Photobiomodulation represented by low level laser and diode laser has a positive effect on promoting the proliferation and differentiation of mesenchymal stem cells. (2) Photobiomodulation can induce osteogenic differentiation of mesenchymal stem cells, whose feasibility has been verified in cell and animal experiments. On one hand, photobiomodulation can promote the expansion and differentiation of stem cells in vitro by activating related signaling pathways and up-regulating the expression of osteogenic molecules. On the other hand, photobiomodulation can improve the survival rate of stem cells in vivo, promote homing effect and shorten the healing time of bone defects after stem cells are injected into the body. However, photobiomodulation has a biphasic dose effect, whose laser parameters, experimental environment, cell type and other factors in various studies are different, making the research results lack consistency and difficult to apply in the clinic. (3) Combined with biological materials, other physical factors and drugs, photobiomodulation can also accelerate osteogenic differentiation. (4) In conclusion, photobiomodulation has been used increasingly widely in the medical field with its advantages of non-invasive, efficient and less-side reactions, and its role in bone tissue engineering has gradually become prominent, which provides a new method for the treatment of bone defects and related diseases. Further exploration should be focused on the standardized treatment parameters of photobiomodulation.
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    Notch signaling pathway regulates proliferation and differentiation of mesenchymal stem cells
    Wang Xuesong, Zhou Lin, Li Lincai, Zou Zhengwei, Tang Xingkun, Lu Wenming, Chen Wenjie, Wang Yue, Ye Junsong
    2024, 28 (19):  3076-3083.  doi: 10.12307/2024.185
    Abstract ( 157 )   PDF (1359KB) ( 20 )   Save
    BACKGROUND: It was found that the ligands and receptors of Notch are both cell membrane surface proteins, which are important proteins to mediate intercellular communication, and the Notch signaling pathway plays a crucial regulatory role in the proliferation and differentiation of mesenchymal stem cells.
    OBJECTIVE: To review the regulatory mechanism of the Notch signaling pathway on the proliferation and differentiation of mesenchymal stem cells, summarize and clarify the research advance in how the Notch signaling pathway regulates the proliferation and differentiation of mesenchymal stem cells, and provide theoretical support for the future use of stem cells to treat various related diseases. 
    METHODS: By using the computer, the first author searched the relevant studies involving Notch signaling pathway regulation of mesenchymal stem cell proliferation and differentiation on CNKI, Wanfang, VIP, PubMed, Web of Science, and Nature databases with Chinese search terms “mesenchymal stem cells, Notch, Notch signaling pathway, proliferation, differentiation” and the English search terms “mesenchymal stem cells, MSC, Notch, Notch signaling pathway, proliferation, differentiation”. Part of the literature was searched in combination with the literature tracing method. Finally, 87 articles were included in the review analysis. 
    RESULTS AND CONCLUSION: (1) Notch signaling pathway is a conserved signaling pathway in multicellular organisms, which plays an important role in regulating cell differentiation, proliferation, apoptosis, and the cell cycle by mediating communication between neighboring cells through receptor-ligand binding. (2) Mesenchymal stem cells are a class of adult stem cells with self-proliferative and multi-directional differentiation potential, which can be regulated by external signaling pathways to affect their proliferation and differentiation. Notch signaling pathway, as one of them, when Notch ligands are activated, the Notch proteins will undergo two protein hydrolysis cleavages to release Notch intracellular structural domain NICD, which then enters the nucleus and thus promotes the transcription of target genes to regulate the proliferation and differentiation of mesenchymal stem cells from different sources, such as bone marrow, adipose, and umbilical cord. However, the specific mechanisms that regulate the proliferation and differentiation of mesenchymal stem cells from different tissue sources of the same species are different. (3) The Notch signaling pathway can regulate the differentiation of mesenchymal stem cells into different target cells, but due to different target cells, the expression levels of receptors or ligands in the Notch signaling pathway vary. (4) Clinical targeting of the Notch signaling pathway to promote mesenchymal stem cells for the treatment of various refractory diseases, such as aplastic anemia, severe joint injuries, ischemic strokes, and myocardial infarctions, has a promising application. (5) By exploring the Notch signaling pathway via regulating the expression levels of its receptors and ligands in bone marrow mesenchymal stem cells from rat, mouse, and human, it can be found that the Notch signaling pathway expression levels in the proliferation and differentiation of mesenchymal stem cells from different species origins are also different. (6) The role of mesenchymal stem cells in tissue engineering has been gradually highlighted due to their advantages of safety, low immune rejection, and wide therapeutic prospects. The Notch signaling pathway regulates the proliferation and differentiation of mesenchymal stem cells with a wide range of influencing factors, and subsequent studies should further optimize the influencing factor variables and explore the standardized studies of regulating the proliferation and differentiation of mesenchymal stem cells. 
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    Effects and problems of growth differentiation factor 5-induced multidirectional differentiation of mesenchymal stem cells
    Li Feifei, Deng Jiang
    2024, 28 (19):  3084-3089.  doi: 10.12307/2024.149
    Abstract ( 159 )   PDF (1009KB) ( 14 )   Save
    BACKGROUND: Growth differentiation factor 5, a member of the transforming growth factor-β superfamily and bone morphogenetic protein family, plays an important role in articular cartilage injury repair, bone regeneration, improvement of intervertebral disc degeneration, tendon healing, and neurodevelopment. 
    OBJECTIVE: To review the research progress of growth differentiation factor 5 in inducing chondrocytes, nucleus pulposus-like cells, tendon cell differentiation, as well as inducing bone formation and neurodevelopment.
    METHODS: The search terms “growth differentiation factor 5, articular cartilage, bone, nucleus pulposus cells, tendon, nerve regeneration” were used in CNKI, WanFang and PubMed. According to the inclusion and exclusion criteria, the articles not related to the subject matter were excluded and 69 articles related to growth differentiation factor 5 were included. 
    RESULTS AND CONCLUSION: (1) Growth differentiation factor 5 can induce chondrogenic and osteoblastic differentiation of mesenchymal stem cells, but the concentration boundary of growth differentiation factor 5 to induce chondrogenic or osteoblastic differentiation remains unclear. (2) Growth differentiation factor 5 can induce mesenchymal stem cells to differentiate into nucleus pulposus cells, which may play a role in the treatment of intervertebral disc degeneration. (3) Growth differentiation factor 5 can induce mesenchymal stem cells to differentiate into tendon cells and play an important role in tendon repair and prevention of postoperative tendon adhesion. (4) Growth differentiation factor 5 can induce neurodevelopment and promote nerve regeneration. 
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    Strategies and advance on stem cell transplantation for repair of spinal cord injury
    He Wanyu, Cheng Leping
    2024, 28 (19):  3090-3096.  doi: 10.12307/2024.145
    Abstract ( 184 )   PDF (1255KB) ( 20 )   Save
    BACKGROUND: Spinal cord injury not only causes serious physical and psychological injuries to patients but also brings a heavy economic burden to society. Spinal cord injury is initially triggered by mechanical trauma, followed by secondary injuries, and as the disease progresses, a glial scar develops.  
    OBJECTIVE: To summarize the pathological process of spinal cord injury and strategies for stem cell transplantation to repair spinal cord injury, aiming to provide the best protocol for treating spinal cord injury.  
    METHODS: Computer search was used to search PubMed and CNKI databases. Chinese search terms were “stem cell transplantation, spinal cord injury”. English search terms were “stem cell, spinal cord injury, spinal cord, mesenchymal stem cells, neural stem cells, pathophysiology, clinical trial, primary injury, secondary injury”. The literature was screened according to the inclusion and exclusion criteria. Finally, 91 articles were included for review analysis. 
    RESULTS AND CONCLUSION: (1) The strategies for repairing spinal cord injury through stem cell transplantation can be divided into exogenous stem cell transplantation and endogenous stem cell transplantation. The exogenous stem cell transplantation strategy for the treatment of spinal cord injury is divided into four kinds: injecting stem cells into the site of injury; transplantation of biomaterials loaded with stem cells; fetal tissue transplantation; transplantation of engineered neural network tissue or spinal cord-like tissue. (2) Compared with a single treatment method, combination therapy can more effectively promote nerve regeneration and spinal cord function recovery. (3) Microenvironment regulating the injury site, magnetic stimulation, electrical stimulation, epidural oscillating electric field stimulation, transcription factor overexpression and rehabilitation therapy can be combined with stem cell transplantation for combination therapy, thereby promoting the recovery of spinal cord function.
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    Improving the strategy of mesenchymal stem cells in treatment of flap ischemia-reperfusion injury
    He Bo, He Zhijun, Li Jinpeng, Liu Tao, Ma Suilu, Wei Xiaotao, Wang Weiwei, Xie Jing
    2024, 28 (19):  3097-3103.  doi: 10.12307/2024.152
    Abstract ( 136 )   PDF (975KB) ( 8 )   Save
    BACKGROUND: Mesenchymal stem cells have great potential in the treatment of ischemia-reperfusion injury of skin flaps. However, their defects and the decline of their role in the treatment of ischemia-reperfusion injury of skin flaps restrict their wide application.
    OBJECTIVE: To review the strategies for improving the treatment of ischemia-reperfusion injury of skin flaps with mesenchymal stem cells, and provide a reference for its further theoretical research and clinical application. 
    METHODS: Relevant documents included in CNKI, WanFang and PubMed were searched. The Chinese and English search terms were “mesenchymal stem cell, ischemia-reperfusion adjustment of skin flap, mesenchymal stem cells, stem cells, skin flap, ischemia-reperfusion injury, pretreatment, gene modification, biomaterial packaging, joint application”. The relevant documents since 2007 were retrieved, and the documents with little relationship between the research content and the article theme, poor quality and outdated content were eliminated through reading the article, and finally 75 documents were included for summary.
    RESULTS AND CONCLUSION: (1) Mesenchymal stem cells can inhibit inflammatory reactions, resist oxidative stress and induce angiogenesis, which has great potential in the treatment of skin flap ischemia-reperfusion injury. (2) Although mesenchymal stem cells have shown great potential in the treatment of skin flap ischemia-reperfusion injury, their shortcomings in treatment have limited their widespread clinical application. Through pre-treatment (cytokines, hypoxia, drugs, and other pre-treatment mesenchymal stem cells), gene-modified mesenchymal stem cells, biomaterial encapsulation of mesenchymal stem cells, as well as the combined use of mesenchymal stem cells and other drugs or therapeutic methods, can not only overcome the shortcomings of mesenchymal stem cells in treatment, but also improve their therapeutic effectiveness in skin flap ischemia-reperfusion injury. (3) Therefore, further improving the effectiveness of mesenchymal stem cells in treating skin flap ischemia-reperfusion injury and exploring its therapeutic potential are of great significance for the research of mesenchymal stem cells and the treatment of skin flap ischemia-reperfusion injury.
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    Exosomes and skin wound healing
    Xiao Ziteng, Wang Tingyu, Zhang Wenwen, Tan Fengyi, Su Haiwei, Li Siting, Wu Yahui, Zhou Yanfang, Peng Xinsheng
    2024, 28 (19):  3104-3110.  doi: 10.12307/2024.144
    Abstract ( 198 )   PDF (1478KB) ( 36 )   Save
    BACKGROUND: Exosomes play a role in all stages of wound repair, and there is currently a large body of research on exosomes in skin wound repair, which has been shown to have great potential for clinical applications. 
    OBJECTIVE: To summarize and discuss the main mechanisms and clinical applications of exosomes in the treatment of skin wounds, in order to promote the clinical translation of exosomes. 
    METHODS: PubMed, clinicaltrials.gov, China National Knowledge Infrastructure, Food and Drug Administration database, and Chinese Clinical Trial Register were searched from inception to March 2023. The English search terms were “exosomes, wound healing, stem cells, chronic wound, immunoregulation, inflammation, skin, therapeutic use, isolation, characterization, infections”. The Chinese search terms were “exosomes, wound healing, stem cells, immunomodulation, clinical applications”. A total of 79 articles were included for the summary. 
    RESULTS AND CONCLUSION: (1) Exosomes can improve and accelerate wound healing through inflammation regulation, immune protection, angiogenesis, cell proliferation and migration, and collagen remodeling. (2) Exosomes derived from stem cells have mature preparation techniques and related mechanism research, which is currently the mainstream research direction. Non-stem cell-derived exosomes have the advantages of convenience, economy, and easy production, and can be used as a supplement for clinical applications. (3) The clinical application of exosomes is still in its infancy, but has great potential for application. Various exosome modification techniques have laid the foundation for the future development of clinically personalized services and require further research. (4) The clinical translation of exosomes faces many challenges, such as low yield, high heterogeneity, lack of unified standards for isolation, purification, and quality control, and difficulties in storage. 
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    Interaction between autophagy and mesenchymal stem cells in treatment of neurodegenerative diseases
    Xiao Yi, Lu Shuo, Ge Lite, Lu Ming
    2024, 28 (19):  3111-3116.  doi: 10.12307/2024.164
    Abstract ( 144 )   PDF (999KB) ( 14 )   Save
    BACKGROUND: Neuronal autophagy disorder and abnormal protein aggregation are the main pathological changes of neurodegenerative diseases. The relationship and interaction between mesenchymal stem cells and autophagy represent a possible mechanism for the treatment of neurodegenerative diseases.
    OBJECTIVE: To review the research progress of autophagy and mesenchymal stem cells in the treatment of neurodegenerative diseases and their interaction in order to provide a theoretical basis and new ideas for the treatment of neurodegenerative diseases.
    METHODS: PubMed and CNKI databases were searched for relevant articles using “autophagy, neurodegenerative diseases, mesenchymal stem cells, Parkinson’s disease, Alzheimer’s disease” as the search terms in Chinese and English. Totally, 59 articles were included for review.
    RESULTS AND CONCLUSION: (1) Autophagy homeostasis is beneficial for maintaining the stability of the internal and external environment of the central nervous system and for controlling the progression of neurodegenerative disease. (2) As a dynamic circulation mechanism to maintain cell renewal and equilibrium, autophagy can affect the biological functions of mesenchymal stem cells such as migration, survival, differentiation, anti-apoptosis and immune regulation, and optimize their therapeutic efficacy for diseases. (3) Mesenchymal stem cells are an important class of neuroprotective agents that can alleviate pathological features and improve dysfunction in neurodegenerative diseases by regulating the level of cellular autophagy, which may be related to specific cellular conditions and activation levels in catabolic processes.
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