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    08 November 2021, Volume 25 Issue 31 Previous Issue    Next Issue
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    Human umbilical cord blood-derived mesenchymal stem cells in the treatment of refractory acute  graft-versus-host disease: a single-arm clinical study
    Xu Huimin, Zhang Suping, Cao Weijie, Li Li, Zhang Ran, Wang Yiran, Wan Dingming
    2021, 25 (31):  4921-4927.  doi: 10.12307/2021.131
    Abstract ( 590 )   PDF (994KB) ( 68 )   Save
    BACKGROUND: Allogeneic hematopoietic stem cell transplantation is an important or even the only potentially curative treatment for many hematological diseases. However, acute graft-versus-host disease is still one of the life-threatening complications after allogeneic hematopoietic stem cell transplantation. There is no standardized treatment for refractory acute graft-versus-host disease. Many studies indicated that mesenchymal stem cells may be used for treating acute graft-versus-host disease through the immunomodulatory effect; however, the actual effect is still to be confirmed.
    OBJECTIVE: To explore the efficacy and safety of human umbilical cord blood-derived mesenchymal stem cells in the treatment of refractory acute graft-versus-host disease and the related factors for the efficacy.
    METHODS:  Totally 24 patients who were diagnosed with refractory acute graft-versus-host disease patients and treated with third-party derived human umbilical cord blood-derived mesenchymal stem cells at the Hematopoietic Stem Cell Transplantation Center of the First Affiliated Hospital of Zhengzhou University were included in the present study. Among them, 8 cases were children, and 16 cases were adults; 10 cases were grade II acute graft-versus-host disease, and 14 cases were grades III-IV. The efficacy, adverse effects, recurrence of primary disease, secondary infection and long-term survival of these patients were observed.  
    RESULTS AND CONCLUSION: (1) The median dose of total infused human umbilical cord blood-derived mesenchymal stem cells was 2.7×106/kg [(2.02-6.00)×106/kg] with a median of 2.5 infusions (range, 2-6 times). The median time from the onset of acute graft-versus-host disease to first human umbilical cord blood-derived mesenchymal stem cells infusion was 12.5 days (range, 8-36 days). (2) The overall response rate at 28 days after infusion was 83% (20/24). The probability of 2-year overall survival was 33.3%. The 2-year overall survival for patients achieving complete remission and partial remission/non-remission were 57% and 0%, respectively (P < 0.000 1). There was significant difference between these two groups. (3) The efficacy for patients with grade II refractory acute graft-versus-host disease was better than grades III-IV (P=0.024). There was no remarkable difference in terms of age, involved organs, primary diseases and the number of infusions of human umbilical cord blood-derived mesenchymal stem cells. (4) In conclusion, treatment with human umbilical cord blood-derived mesenchymal stem cells is a safe and effective option for patients with refractory acute graft-versus-host disease.
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    Immunomodulatory effects of umbilical cord-mesenchymal stem cells modified by miR-1-5p on T lymphocyte subsets in systemic lupus erythematosus
    Hu Mingzhi, Zhang Jingying, Yang Guoan, Pang Chunyan, Zhang Wei, Wang Yongfu, Sun Xiaolin
    2021, 25 (31):  4928-4938.  doi: 10.12307/2021.132
    Abstract ( 513 )   PDF (2635KB) ( 131 )   Save
    BACKGROUND: In recent years, there were lots of researches on the treatment of diseases by gene modified mesenchymal stem cells, including the treatment of autoimmune diseases. Various miRNAs have been found to be abnormally expressed in autoimmune diseases, among which miR-1 is low-expressed in polymyositis, and miR-1-3p is one of the miRNAs related to systemic lupus eythematosus susceptibility genes.  
    OBJECTIVE: To investigate the immunoregulatory effect of miR-1-5p modified umbilical cord-mesenchymal stem cells on T lymphocyte subsets in systemic lupus erythematosus.
    METHODS:  The expression level of miR-1-5p in the two groups was detected by real-time fluorescence quantitative PCR in eight patients aged 30-60 years with active systemic lupus erythematosus and eight healthy subjects. Umbilical cord-mesenchymal stem cells were isolated and cultured from umbilical cord of newborns delivered at term or cesarean section under aseptic conditions. Using the liposome method, the umbilical cord-mesenchymal stem cells were transfected with Red Fluorescent Control with a concentration gradient of 5, 7, 10, and 15 nmol/L for 24, 48, and 72 hours. Transfection efficiency of miR-1-5p was determined by flow cytometry at different concentration gradients and time gradients. Peripheral blood mononuclear cells in systemic lupus erythematosus patients were isolated by density gradient centrifugation and co-cultured with umbilical cord-mesenchymal stem cells which were transfected with miR-1-5p, and divided into four groups: umbilical cord-mesenchymal stem cells transfected with miR-1 and co-cultured with peripheral blood mononuclear cells of systemic lupus erythematosus patients, umbilical cord-mesenchymal stem cells transfected with miRNA negative control and co-cultured with peripheral blood mononuclear cells of systemic lupus erythematosus patients, umbilical cord-mesenchymal stem cells co-cultured with peripheral blood mononuclear cells of systemic lupus erythematosus patients, and peripheral blood mononuclear cells of systemic lupus erythematosus patients without treatment group. The co-culture was conducted for 48 hours. The relative expression levels of IL-17A, Foxp3, IFN-γ and IL-4 genes in each group were detected by real-time fluorescence quantitative PCR. Flow cytometry was used to detect the differentiation of Th17, Treg, Th1 and Th2 cells in peripheral blood mononuclear cells of each group. 
    RESULTS AND CONCLUSION: (1) miR-1-5p was significantly down-regulated in peripheral blood mononuclear cells of systemic lupus erythematosus patients compared with healthy controls (P < 0.05). (2) The transfection efficiency was highest when the concentration of miR-1-5p was 10 nmol/L and the transfection time was 48 hours. (3) Compared with the peripheral blood mononuclear cells of systemic lupus erythematosus patients without treatment group, the expression of Foxp3 in umbilical cord-mesenchymal stem cells transfected with miR-1-5p and co-cultured with peripheral blood mononuclear cells of systemic lupus erythematosus patients group was increased; the proportion of Treg cells was significantly increased; and the differences were statistically significant (P < 0.05). Compared with the peripheral blood mononuclear cells of systemic lupus erythematosus patients without treatment group, Th17/Treg ratio decreased in the other three co-culture groups, and the difference was statistically significant (P < 0.01). Th17/Treg cell ratio detected by flow cytometry in each group was not significantly different (P > 0.05). Compared with the peripheral blood mononuclear cells of systemic lupus erythematosus patients without treatment group, the Th1/Th2 ratio in the umbilical cord-mesenchymal stem cells transfected with miR-1-5p and co-cultured with PBMC of systemic lupus erythematosus patients group decreased, and the difference was statistically significant (P < 0.05). However, the Th1/Th2 cell ratio of each group detected by flow cytometry was not significantly different (P > 0.05). (4) The results showed that the umbilical cord-mesenchymal stem cells modified by miR-1-5p had an immunoregulatory effect on Treg cells of systemic lupus erythematosus, and overexpression of miR-1-5p could promote the differentiation and proliferation of Treg cells of systemic lupus erythematosus patients. miR-1-5p regulates the immune imbalance of Th17/Treg and Th1/Th2 by up-regulating the expression of Treg cells. 

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    Effect of over expression of miR-378a on osteogenic and vascular differentiation of bone marrow mesenchymal stem cell sheet
    Li Jun, Zuo Xinhui, Liu Xiaoyuan, Zhang Kai, Han Xiangzhen, He Huiyu,
    2021, 25 (31):  4939-4944.  doi: 10.12307/2021.133
    Abstract ( 482 )   PDF (3006KB) ( 57 )   Save
    BACKGROUND:  In recent years, the use of microRNAs to regulate the function and differentiation of stem cells is an attractive treatment model for regenerative medicine. Therefore, loading microRNA with stem cell sheet and to enhance its osteogenesis and angiogenesis properties is of great significance to develop a new type of repair material for bone defect.
    OBJECTIVE: To investigate the effect of over expression of miR-378a gene on the osteogenic and angiogenic differentiation of bone marrow mesenchymal stem cell sheet.
    METHODS:  Bone marrow mesenchymal stem cells from Sprague-Dawley rats were isolated and cultured. miR-378a lentivirus vector and negative control virus with appropriate titers were selected to infect bone marrow mesenchymal stem cells, which were recorded as LV-miR-378a-BMMSCs group and LV-BMMSCs group in turn, and cells not transfected with viral vector were used as blank group. Three groups of cells were inoculated into a six-well plate, and the membrane induced liquid was added for culture for 6 days. The morphology of the membrane was observed under the microscope. After the formation of the membrane, the membrane was cultured by osteogenic induction culture. At 3, 7, and 14 days of culture, the mRNA expressions of miR-378a, osteogenic gene runt-related transcription factor 2 (RUNX2) and type I collagen, angiogenesis genes vascular endothelial growth factor and platelet growth factor were detected by RT-PCR. Western blot assay was used to detect the protein expression of RUNX2 and vascular endothelial growth factor when cultured for 14 days.  
    RESULTS AND CONCLUSION: (1) On day 2 after the induction of membrane formation, a small amount of stroma was observed to be connected between the central spindle cells of the membrane microscopically, and the edge of the membrane was furred and discontinuous. On day 6, the central cells of the membrane were overlapped and dense, and a large number of cell matrix networks were cross-connected. The edges of the membrane showed continuous and widened folds and rolled toward the center, showing no significant difference from the morphological changes of the blank group. (2) The mRNA expressions of miR-378a, RUNX2, type I collagen, vascular endothelial growth factor and platelet growth factor at each time points in the LV-miR-378a-BMMSCs group were higher than those in the LV-BMMSCs group and the blank group (P < 0.001), and the protein expressions of RUNX2 and vascular endothelial growth factor were all higher than those in LV-BMMSCs group (P < 0.001) and blank group (P < 0.01). (3) The results showed that overexpression of miR-378a promoted the osteogenesis and angiogenesis of the bone marrow mesenchymal stem cell sheet in vitro.
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    Exosomes from human umbilical cord-derived mesenchymal stem cells suppress the proliferation and promote the apoptosis of medulloblastoma Daoy cells
    Yi Zhishuang, Wang Zhihai, Li Ming, Zhou Qingan, Yang Baosheng
    2021, 25 (31):  4945-4949.  doi: 10.12307/2021.134
    Abstract ( 390 )   PDF (1518KB) ( 76 )   Save
    BACKGROUND:  Mesenchymal stem cells can produce a large number of exosomes, which has similar biological activity to mesenchymal stem cells. However, the effect of mesenchymal stem cell-derived exosomes on Daoy cells of medulloblastoma has yet to be determined.
    OBJECTIVE: To investigate the effect of exosomes derived from human umbilical cord-derived mesenchymal stem cells on the proliferation and apoptosis of medulloblastoma Daoy cells and its potential mechanism.
    METHODS:  Human umbilical cord-derived mesenchymal stem cells were isolated and cultured. Passage 4 of human umbilical cord-derived mesenchymal stem cells was collected. The expression of exosome markers CD9 and CD81 was detected by western blot assay. Exosomes extracted from human umbilical cord-derived mesenchymal stem cells were cocultured with Daoy cells for 96 hours. The proliferation of Daoy cells was detected by flow cytometry and colony formation assay. The apoptosis of Daoy cells was detected by flow cytometry. The expression levels of apoptosis related proteins were detected by western blot assay.  
    RESULTS AND CONCLUSION: Western blot assay results showed that exosomes from human umbilical cord-derived mesenchymal stem cells were positive for CD9 and CD81. Compared with the control group, exosomes from human umbilical cord-derived mesenchymal stem cells inhibited the proliferation of Daoy cells and the formation of colonies (P < 0.05, P < 0.01), and promoted Daoy cell apoptosis (P < 0.01). Apoptosis related proteins Cyclin D1 and Bcl-2 were down regulated (P < 0.05), but expression level of Caspase-3 was up-regulated (P < 0.01). The results confirm that human umbilical cord-derived mesenchymal stem cells derived exosomes can suppress the proliferation of Daoy cells and promote its apoptosis possibly by regulating cell cycle and apoptosis related protein expression. 

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    Low-intensity pulsed ultrasound mediates bone marrow mesenchymal stem cells to promote osteoarthritis cartilage repair
    Liao Qing, Li Baojian, Li Yang, Xu Taixiang, Zeng Jing, Zhang Zhenzhen, Liu Gang
    2021, 25 (31):  4950-4955.  doi: 10.12307/2021.135
    Abstract ( 519 )   PDF (2769KB) ( 175 )   Save
    BACKGROUND: Studies have shown that bone marrow mesenchymal stem cells and low-intensity pulsed ultrasound can promote the repair of knee osteoarthritis cartilage, but there is no report whether low-intensity pulsed ultrasound-mediated bone marrow mesenchymal stem cells can have a better effect on knee osteoarthritis cartilage repair.
    OBJECTIVE: To observe the repair effect of bone marrow mesenchymal stem cells mediated by low-intensity pulsed ultrasound on knee osteoarthritis cartilage.
    METHODS:  Totally 36 Sprague-Dawley male rats aged 6 weeks were randomly divided into four groups: control group, osteoarthritis group, stem cell group and stem cell plus ultrasound group (n=9 per group). In the osteoarthritis group, stem cell group and stem cell plus ultrasound group, osteoarthritis models were made by the anterior cruciate ligament transection of the right knee joint with partial resection of the medial meniscus. At 6 weeks after model establishment, no special treatment was given to the control group and the osteoarthritis group. In the stem cell group and the stem cell plus ultrasound group, the knee joint cavity was injected with bone marrow mesenchymal stem cells 0.1 mL (cell concentration was 1×109 L-1), once a week, for 4 weeks. Simultaneously, rats in the stem cells plus ultrasound group were treated with low-intensity pulsed ultrasound at 20 minutes/day for 4 weeks. Western blot assay was used to detect the expression of type II collagen and Sox9 protein in rat articular cartilage, and Mankin score was used to evaluate the degree of cartilage degeneration in each group of experimental rats. 
    RESULTS AND CONCLUSION: (1) After 4 weeks of treatment, the expression of type II collagen and Sox9 protein in the osteoarthritis group was reduced compared to the other three groups (P < 0.05). The protein expression of type II collagen and Sox9 in the stem cell group was lower than that of stem cells plus ultrasound group (P < 0.05). (2) The Mankin scores of control group, stem cell group and stem cell plus ultrasound group were significantly lower than those of the osteoarthritis group (P < 0.01). Compared with the stem cell group, the Mankin score of the stem cell plus ultrasound group was lower (P < 0.05). (3) The results show that compared with simple bone marrow mesenchymal stem cells, low-intensity pulsed ultrasound-mediated bone marrow mesenchymal stem cells have a better effect on cartilage repair in knee osteoarthritis.
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    Treatment of knee osteoarthritis with human umbilical cord-derived mesenchymal stem cells combined with sodium hyaluronate injection
    Cui Xiaoyan
    2021, 25 (31):  4956-4963.  doi: 10.12307/2021.136
    Abstract ( 559 )   PDF (4074KB) ( 105 )   Save
    BACKGROUND: Knee osteoarthritis seriously affects the living quality of patients and there is still no optimal treatment.
    OBJECTIVE: To evaluate the efficacy and safety of human umbilical cord-derived mesenchymal stem cells combined with hyaluronic acid on the treatment of knee osteoarthritis.
    METHODS:  (1) Cytological experiments were carried out to observe the effect of human umbilical cord-derived mesenchymal stem cells on lymphocyte proliferation and proportion of regulatory T cells. (2) The effects of premixed sodium hyaluronate on adipogenesis and chondrogenesis of human umbilical cord-derived mesenchymal stem cells were observed by oil red O staining and alcian blue staining. (3) Rabbit osteoarthritis was induced surgically by anterior cruciate ligament transection and medial meniscectomy of right knee joints. The intra-articular injection was given at 6, 9 and 12 weeks after surgery of human umbilical cord-derived mesenchymal stem cells, sodium hyaluronate injection, umbilical cord-derived mesenchymal stem cells combined with sodium hyaluronate injection. All rabbits were sacrificed at 16 weeks after surgery. The specific FOXP2 gene was measured in the heart, liver, spleen, lung, kidney, brain, muscles around the joint cavity, and knee joint with qPCR method. The morphological, histological and immunohistochemical analyses were carried out to detect the cartilage repair of femoral condyles. 
    RESULTS AND CONCLUSION: (1) Human umbilical cord-derived mesenchymal stem cells suppressed T lymphocyte proliferation and upregulated proportion of regulatory T cells. (2) Human umbilical cord-derived mesenchymal stem cells premixed with sodium hyaluronate still retained the property of adipogenesis and chondrogenesis. (3) At 16 weeks after treatment, the human specific gene FOXP2 was all negative in the heart, liver, spleen, lung, kidney, brain and muscles around the joint cavity of rabbits. (4) The articular surface of human umbilical cord-derived mesenchymal stem cells + sodium hyaluronate group was flat and smooth, and the ICRS score was significantly higher than that of the sodium hyaluronate group. Hematoxylin-eosin staining results showed that cartilage thickness was increased and the Pineda score of human umbilical cord-derived mesenchymal stem cells + sodium hyaluronate group was significantly lower than that of the sodium hyaluronate group and the human umbilical cord-derived mesenchymal stem cells group. The whole cartilage layer of human umbilical cord-derived mesenchymal stem cells + sodium hyaluronate group contained more proteoglycans. The OARSI score of human umbilical cord-derived mesenchymal stem cells + sodium hyaluronate group was significantly lower than that of the sodium hyaluronate group and the human umbilical cord-derived mesenchymal stem cells group. Immunohistochemical analysis showed that the expression of type II collagen in articular cartilage was increased and the expression of matrix metalloproteinase-13 was decreased. (5) The results indicate that human umbilical cord-derived mesenchymal stem cells combined with sodium hyaluronate treatment were superior to either sodium hyaluronate treatment alone or human umbilical cord-derived mesenchymal stem cells treatment alone in articular cartilage repair and there was no significant adverse reaction.
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    Bone marrow mesenchymal stem cell derived exosomes delay the occurrence and development of osteoarthritis through cartilage protection
    Ling Huajun, Wang Qiyou, Lin Weiwen, Luo Penggang
    2021, 25 (31):  4964-4969.  doi: 10.12307/2021.137
    Abstract ( 548 )   PDF (3097KB) ( 70 )   Save
    BACKGROUND: Osteoarthritis is the most common joint degenerative disease. At present, bone marrow mesenchymal stem cells have been used in the treatment of osteoarthritis. However, compared with bone marrow mesenchymal stem cells, bone marrow mesenchymal stem cell derived exosome transplantation has more advantages, such as non-immunogenicity, non-tumorigenicity, convenient storage and transportation.
    OBJECTIVE: To explore the protective effect of bone marrow mesenchymal stem cell exosomes on osteoarthritis. 
    METHODS:  (1) SD rat bone marrow mesenchymal stem cells were extracted and identified by cell morphology and flow cytometry. Exosomes in the cell supernatant were extracted by ultracentrifugation and identified by transmission electron microscopy, particle size and western blot assay. (2) Primary costal chondrocytes were extracted from suckling rats and cocultured with fluorescently labeled exosomes for 12 hours. The phagocytosis of chondrocytes was observed. In vitro chondrocyte damage was induced by interleukin-1β. PBS (100 μL) containing 50 μg exosomes was added for 24 hours. The expression of matrix metalloproteinase-13 and type II collagen fiber α1 protein was detected by immunofluorescence to evaluate the protective effect of exosomes on injured chondrocytes. (3) The rat model of osteoarthritis was induced by iodoacetic acid in vivo. Exosomes were injected into the joint cavity, and the changes of joint structure of osteoarthritis were observed by hematoxylin-eosin staining and safrane-fast green staining. The expression of matrix metalloproteinase-13 and type II collagen fiber α1 protein was measured by immunohistochemical staining to evaluate the protective effect of exosomes on cartilage in vivo. 
    RESULTS AND CONCLUSION: (1) The extracted primary cells showed a typical fusiform shape and arranged radially. The extracted cells highly expressed CD73 and CD105, but slightly expressed CD45, CD34 and CD3. Transmission electron microscopy showed that the obtained particles showed a typical saucer-like morphology. The particle size was less than 100 nm. Meanwhile, nanoparticles showed positive expression of ALIX and HRS protein. (2) Typical red-stained particles could be observed in chondrocytes, which confirms that exosomes could be taken up by chondrocytes, and exosomes could promote chondrocyte type II collagen fiber α1 protein expression, but inhibit the expression of matrix metalloproteinase-13, which confirmed that exosomes could attenuate the damage effect of interleukin-1β on chondrocytes. (3) Exosomes could promote the morphological recovery of damaged articular cartilage and the up-regulate type II collagen fiber α1 expression, while inhibited the expression of matrix metalloproteinase-13, which also confirmed that exosomes can alleviate the effects of iodoacetic acid on articular cartilage damage. (4) Above findings results indicate that bone marrow mesenchymal stem cell exosomes delay the occurrence and development of osteoarthritis through a chondroprotective mechanism.
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    Human placenta-derived mesenchymal stem cell conditioned medium can upregulate BeWo cell viability and zonula occludens expression under hypoxia
    Lin Qingfan, Xie Yixin, Chen Wanqing, Ye Zhenzhong, Chen Youfang
    2021, 25 (31):  4970-7975.  doi: 10.12307/2021.138
    Abstract ( 271 )   PDF (2110KB) ( 90 )   Save
    BACKGROUND: In recent years, mesenchymal stem cells have become a research hotspot in the field of new drug development, and their paracrine effect has also been applied in the repair evaluation experiments of a variety of tissue injured cell models, but there is no research to explore whether their conditioned medium can repair the tight junction function of human placental trophoblast cells under hypoxia.
    OBJECTIVE: To demonstrate the effect of mesenchymal stem cell conditioned medium on cell viability and expression of tight junction factors in human placental choriocarcinoma trophoblast cell line BeWo under hypoxia. 
    METHODS: BeWo cells were exposed to hypoxia induced by 1 000 μmol/L CoCl2 for 12 hours to construct the hypoxia model of placental barrier. For model evaluation, five indexes were measured, including cell viability and expression of hypoxia induced factors-1α, as well as three tight junction factors: zonula occludens 1, claudins 4 and claudins 8. Mesenchymal stem cell conditioned medium was added into hypoxia model to construct hypoxia intervention and reoxygenation groups. To investigate the potential mechanism of zonula occludens 1 expression recovery induced by mesenchymal stem cell conditioned medium, insulin-like growth factor 1 hypoxia intervention and treatment groups were established, and the BeWo cell viability and zonula occludens 1 expression were detected.   
    RESULTS AND CONCLUSION: (1) BeWo cells viability, zonula occludens 1 and claudins 4 expression were reduced by CoCl2-mimic hypoxia, with hypoxia induced factors-1α mRNA and protein upregulation. However, the expression of claudins 8 mRNA was upregulated, and its protein was downregulated. (2) Human placenta-derived mesenchymal stem cell conditioned medium improved BeWo cells viability and recovered expression level of hypoxia induced factors-1α and zonula occludens 1 under hypoxia induced by CoCl2, but it has no effect on claudins 4. (3) Insulin like growth factor-1 intervention alleviated the inhibition of hypoxia on the viability of BeWo cells, and upregulated the expression of zonula occludens 1.
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    Effect of hydrostatic pressure on odontogenic/osteogenic differentiation of dental pulp stem cells
    Li Junqing, He Wenxi, Guo Qian, Wu Jiayuan
    2021, 25 (31):  4976-4980.  doi: 10.12307/2021.139
    Abstract ( 484 )   PDF (1670KB) ( 53 )   Save

    BACKGROUND: Besides biochemical factors, cellular mechanics is increasingly recognized as the key factor affecting the behavior and function of stem cells. 

    OBJECTIVE: To explore the effect of hydrostatic pressure on the odontogenic/osteogenic differentiation potential of human dental pulp stem cells. 
    METHODS:  Human dental pulp stem cells were isolated and extracted by enzyme digestion. The expression of cell surface markers was detected by flow cytometry. After osteogenic induction for 14 days or adipogenic induction for 21 days, alizarin red or oil red O staining was used to identify the mutidirectional differentiation of human dental pulp stem cells. The human dental pulp stem cells were loaded with hydrostatic pressure of different pressure values (0, 30, 60, 90, 120, and 150 kPa) by using the self-developed mechanical loading device, for 1 hour. At 1, 3, 5, and 7 days, the culture solution was discarded. CCK-8 assay was used to observe the proliferation of human dental pulp stem cells, 1 hour per day, for 14 consecutive days. Alizarin red staining was applied to observe the osteogenic and mineralized abilities. Western blot assay was used to detect the protein expression levels of odontogenic/osteogenic differentiation related genes.   
    RESULTS AND CONCLUSION: Dental pulp stem cells expressed high levels of CD29, CD90, CD146, CD105 and low levels of CD45 and CD34, and had the ability of osteogenic and adipogenic differentiation. Hydrostatic pressure could promote the proliferation of human dental pulp stem cells at 90 and 120 kPa, but the proliferation ability could be significantly inhibited when the pressure value was 150 kPa. After 14 days of hydrostatic pressure stimulation, the protein expression levels of dentin sialophosphoprotein, collagen type I, and osteocalcin in dental pulp stem cells were significantly lower than those in the control group (P < 0.05), and their ability to inhibit differentiation became more obvious with the increase of hydrostatic pressure. The results show that hydrostatic pressure is involved in the process of dental pulp stem cell odontogenesis/osteogenesis and has a negative regulatory effect.

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    Radial extracorporeal shock wave therapy promotes the proliferation of neural stem cells in hippocampus of cerebral infarction rats and inhibits miR-124 expression
    Li Jie, Ma Yuewen, Kang Nan, Zhang Jing, Zhang Yu
    2021, 25 (31):  4981-4987.  doi: 10.12307/2021.140
    Abstract ( 438 )   PDF (1932KB) ( 76 )   Save
    BACKGROUND: miR-124 plays an important role in the proliferation of neural stem cells and changes in brain tissue and blood expression after cerebral infarction, suggesting that it is one of the core regulators of endogenous nerve regeneration after cerebral infarction. Radial extracorporeal shock wave therapy can promote neural stem cell proliferation, but whether it is related to miR-124 is currently unclear. 
    OBJECTIVE: To investigate the effect of radial extracorporeal shock wave therapy on the expression of miR-124 in the hippocampus after cerebral infarction and whether the promotion of neural stem cell proliferation is related to miR-124.
    METHODS:  A model of middle cerebral artery occlusion in rats was established. Rats were randomly divided into radial extracorporeal shock wave group and control group. The radial extracorporeal shock wave group was subjected to radial extracorporeal shock wave therapy intervention, with the ischemic head 72 hours after the cerebral infarction, once every 3 days. At 11, 20, 29, and 38 days after model establishment, modified neurological function scores were assessed in rats. Then RT-qPCR was used to detect the expressions of miR-124 and Nestin mRNA in the hippocampus of cerebral infarction rats. Western blot assay and immunofluorescence were used to detect the expression of Nestin protein in the hippocampus of the ischemic side.   
    RESULTS AND CONCLUSION: (1) After cerebral infarction in rats, the expression of miR-124 gradually increased in the hippocampus of the ischemic side. (2) At 11, 20, 29, and 38 days after middle cerebral artery occlusion, the neurological scores of the rats were lower in the radial extracorporeal shock wave group than those in the control group (P < 0.05). The expression of Nestin was higher on the ischemic side of the hippocampus than that in the control group (P < 0.05). (3) At 11, 20 and 29 days after middle cerebral artery occlusion, the expression of miR-124 in hippocampus of cerebral infarction rats on the affected side in the radial extracorporeal shock wave group was lower than that of the control group (P < 0.05). (4) Results suggest that expression of miR-124 in the hippocampus of cerebral infarction rats is increased. Radial extracorporeal shock wave therapy directly interfering with the head of the affected side can reduce the expression of miR-124, increase the number of neural stem cells, and improve impaired nerve function. 
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    Effect of xanthohumol on proliferation, migration, tube formation and apoptosis of endothelial progenitor cells and its mechanism
    Tan Xiaowu, Yu Xiaofan, Jiang Huijiao, Xing Zhikun, Zhao Xueyuan, Gao Fengyi, Wu Xiangwei, Chen Xueling
    2021, 25 (31):  4988-4994.  doi: 10.12307/2021.141
    Abstract ( 411 )   PDF (4230KB) ( 111 )   Save
    BACKGROUND: The development of tumor depends on angiogenesis to transport oxygen and micronutrients, and promote its metastasis. The neovessels in tumor is considered to be the new capillaries formed by the migration and proliferation of endothelial cells in the original vascular system. More and more evidence shows that bone marrow-derived endothelial progenitor cells contribute to neovascularization and have become an important target for anti-tumor therapy. In previous studies, there was no report about the effect of xanthohumol on bone marrow-derived endothelial progenitor cells.
    OBJECTIVE: To study the effects of xanthohumol on the proliferation, migration, tube formation and apoptosis of bone marrow-derived endothelial progenitor cells, and to preliminarily explore its mechanism of action. 
    METHODS:  The third passage of bone marrow-derived endothelial progenitor cells were divided into four groups: 5, 10, 20 μmol/L xanthohumol group and the same amount of dimethyl sulfoxide solution as the control group. After intervention for 24 and 48 hours, effect of xanthohumol on the proliferation of bone marrow-derived endothelial progenitor cells was measured by the CCK-8 method. After intervention for 24 hours, the scratch test and the Transwell test were used to detect the effect of xanthohumol on the migration of mouse bone marrow-derived endothelial progenitor cells. After intervention for 6 hours, the tube test was used to detect the effect of xanthohumol on the lumen formation of mouse bone marrow-derived endothelial progenitor cells. After intervention for 48 hours, flow cytometry and TUNEL assay were applied to detect the effect of xanthohumol on the apoptosis of mouse bone marrow-derived endothelial progenitor cells. After intervention for 48 hours, western blot assay was employed to detect the effect of xanthohumol on vascular endothelial growth factor, vascular endothelial growth factor receptor 2, P65 and p-P65 protein.   
    RESULTS AND CONCLUSION: (1) After the intervention of xanthohumol, the half maximal inhibitory concentration (IC50) of bone marrow-derived endothelial progenitor cells at 24 and 48 hours were (22.19±0.98) and (11.51±1.25) μmol/L, respectively. The comparison between them was statistically significant (P < 0.05), indicating that xanthohumol could significantly inhibit the proliferation of bone marrow-derived endothelial progenitor cells in a certain dose-effect relationship (P < 0.05). (2) Compared with the control group, as the concentration of xanthohumol increases, the scratches were more obvious (P < 0.05), and the number of migrating cells decreased gradually (P < 0.05). (3) A large number of tubule-like structures were formed in the control group, while the tubule-like structures were significantly reduced in the 5 and 10 μmol/L xanthohumol groups, and no tubule-like structures were formed in the 20 μmol/L xanthohumol group, with significant difference compared with the control group (P < 0.05). (4) The apoptosis rate was significantly increased after xanthohumol treatment in a concentration-dependent manner, and the apoptosis rate in each xanthohumol group was significantly higher than that in the control group (P < 0.05). (5) Compared with the control group, with the increase of xanthohumol concentration, the expression of p-P65 and vascular endothelial growth factor decreased, while vascular endothelial growth factor receptor 2 increased in a concentration-dependent manner (P < 0.05). (6) These results indicate that xanthohumol can inhibit the proliferation, migration, tube formation and apoptosis of bone marrow-derived endothelial progenitor cells. The mechanism may be through the inhibition of NF-κB/vascular endothelial growth factor signaling pathway, indicating that xanthohumol has the potential of anti-tumor angiogenesis.
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    Changes in biological characteristics of platelet-rich fibrin by freeze-drying technology
    Liu Lei, Di Haiping, Guo Haina, Cao Dayong, Niu Xihua, Xia Chengde
    2021, 25 (31):  4995-4999.  doi: 10.12307/2021.142
    Abstract ( 396 )   PDF (1386KB) ( 47 )   Save
    BACKGROUND: Platelet-rich fibrin has been used in bone and soft tissue repair in clinic. However, due to its biological activity, it is limited to short-term clinical application. Therefore, how to keep platelet-rich fibrin stably and prolong the time of clinical application is very important.  
    OBJECTIVE: To explore the effect of freeze-drying technology on the morphology of  platelet-rich fibrin and the activity and release regularity of growth factor releasing from platelets in platelet-rich fibrin. 
    METHODS:  Fresh and freeze-dried platelet-rich fibrin were prepared and then soaked in DMEM basic medium without fetal bovine serum. The supernatant of freeze-dried or fresh platelet-rich fibrin was collected at 1, 7, 14 and 21 days and used for fibroblast culture and platelet-derived growth factor-BB content determination. The morphological structure, activity and release regularity of growth factor releasing from platelets in platelet-rich fibrin were compared before and after freeze-drying. Morphological observation was detected by hematoxylin-eosin staining. Cell proliferation was measured by CCK8 assay. The cell migration ability was evaluated by cell scratch test. Platelet-derived growth factor-BB content of collected supernatant at different time points in the two groups was detected by using ELISA kit.  
    RESULTS AND CONCLUSION: (1) Hematoxylin-eosin staining showed that the structure of freeze-dried platelet-rich fibrin was loose and spongy, and the pore diameter was large. The number of nuclear cells in blue staining was significantly reduced. (2) Compared with the serum-free medium, the fresh and freeze-dried platelet-rich fibrin extracts collected on the 1 and 7 days significantly promoted the proliferation of fibroblasts (P < 0.05), and freeze-dried platelet-rich fibrin extracts strongly promoted the proliferation capacity of fibroblasts (P < 0.05). (3) Compared with the serum-free medium, the fresh and freeze-dried platelet-rich fibrin extract, and the complete medium containing 10% fetal bovine serum could effectively promote the migration of fibroblasts at 12 and 24 hours, and the difference was statistically significant (P < 0.05). (4) Compared with the fresh platelet-rich fibrin, the freeze-dried platelet-rich fibrin showed higher migration ability of fibroblasts at 12 and 24 hours (P < 0.05), and the difference was statistically significant (P < 0.05). (5) The content of platelet-derived growth factor-BB in fresh platelet-rich fibrin group was the largest at 7 days, and the release of growth factor gradually decreased. The content of platelet-derived growth factor-BB in freeze-dried platelet-rich fibrin group was the largest at 1 day, and the release of growth factor gradually decreased with time, and the difference was statistically significant (P < 0.05). The total content of platelet-derived growth factor-BB showed no significant difference between the two groups (P > 0.05). (6) The results show that freeze-drying technology is feasible for platelet-rich fibrin preservation, which can provide theoretical basis for tissue repair and reconstruction.
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    Current states and tendency of stem cells in the treatment of intervertebral disc degeneration: bibliometric analysis
    Li Qiujiang, Fang Xiaomin, Wang Yinbin, Hu Xuehua, Cai Lijun
    2021, 25 (31):  5000-5011.  doi: 10.12307/2021.143
    Abstract ( 499 )   PDF (4220KB) ( 206 )   Save
    BACKGROUND: The treatment of stem cells in intervertebral disc degeneration has always been a research hotspot. It is possible to predict and analyze the research status and development trend of this field to a certain extent, applying bibliometric analysis software to perform co-occurrence and co-citation analysis of numerous literature data in this field.
    OBJECTIVE: To analyze research status and development trend of stem cells in the treatment of intervertebral disc degeneration by bibliometric visualization analysis.
    METHODS: The authors retrieved the literature on stem cells in the treatment of intervertebral disc degeneration from 1999 to 2020 through the core collection of Web of Science, and used bibliometrics methods to conduct statistical analysis on the literature data, combined with Citespace 5.6.R5 and VOSviewer 1.6.15 software to transform the visualization atlas, analyze the research status and development trend of stem cells in the treatment of intervertebral disc.   
    RESULTS AND CONCLUSION: (1) A total of 613 articles were included. The number of publications of stem cells in intervertebral disc treatment research is increasing year by year. Among them, China and the United States rank first and second with 232 and 174 publications respectively. (2) The United States has a total citation frequency (5 522), h index (42), and betweenness centrality (0.75) ranks first, both higher than the second place in China (3 169, 28, 0.16). (3) The top ten cited references introduced the research on the treatment of intervertebral disc degeneration with microscopic mesenchymal stem cells from various aspects, and seven of them were related to nucleus pulposus like differentiation of bone marrow mesenchymal stem cells. Two papers are related to the best cell source and cell carrier generation in the treatment of intervertebral disc regeneration. One is related to the clinical trial study of the treatment of degenerative disc regeneration. (4) The timeline chart of reference co-citation shows that the most references are published in clusters of “Mesenchymal Stem Cells”, “Notochord Cells”, “End Plates”, and “Adipose derived Mesenchymal Stem Cells”. From a year of publication perspective, the clustering “notochord cells”, “notochord”, and “injection” published in the latest year. (5) Clustering keywords “intervertebral disc degeneration”, “migration”, “notochord cells”, “genipin” and “hydrogel” correspond exactly to the above. It was confirmed that the keywords suddenly appeared and found that present research hotspots are: mesenchymal stem cell nucleus pulposus-like differentiation, the best cell source in the treatment of intervertebral disc regeneration and the clinical effectiveness and biosafety of cell carrier construction and intervertebral disc regeneration treatment. (6) There are five new keywords from 2017 to 2019, namely “injection”, “intervertebral disc degeneration”, “inflammation”, “apoptosis”, and “puncture”, mainly focusing on cell apoptosis, inflammatory reaction, intervertebral disc regression, and cell transplantation methodology. (7) The above-mentioned global trend analysis suggests that as the amount of stem cells published in the treatment of intervertebral disc degeneration continues to increase, related research is also constantly deepening. The current research focuses on the nucleus pulposus-like differentiation of mesenchymal stem cells, the best cell source and cell carrier integration in the treatment of intervertebral disc regeneration, and the clinical effectiveness and biological safety of integration of intervertebral disc regeneration treatment. In-depth exploration of the mechanism of intervertebral disc degeneration and inflammatory response and improvement of cell transplantation methodology are the focus of future research.

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    Fasudil inhibits lipopolysaccharide-induced astrocytic injury by regulating Nrf2/HO-1 signaling pathway
    Guo Minfang, Zhang Huiyu, Zhang Peijun, Bai Zhenjun, Yu Jingwen, Wang Yuyin, Wei Wenyue, Song Lijuan, Chai Zhi, Yu Jiezhong, Ma Cungen
    2021, 25 (31):  5012-5017.  doi: 10.12307/2021.144
    Abstract ( 517 )   PDF (2125KB) ( 103 )   Save
    BACKGROUND: More and more evidences show that ROCK signaling pathway is involved in inflammation and oxidative stress. Fasudil is an effective Rho kinase inhibitor. Our previous series of studies have proved that fasudil has neuroprotective effects. However, it is still unclear that whether fasudil has protective effect on oxidative damage to astrocytes and its possible mechanisms.
    OBJECTIVE: To explore the protective effect and mechanism of fasudil on lipopolysaccharide-induced oxidative injury in astrocytes.
    METHODS: Primary C57BL/6 mouse astrocytes were cultured and divided into PBS control group, lipopolysaccharide stimulation group (1 mg/L), lipopolysaccharide (1 mg/L) combined with fasudil (15 mg/L) treatment group. After 24 hours of treatment, MTT assay was used to detect the viability of astrocytes. The content of malondialdehyde and the activity of superoxide dismutase in astrocytes were measured using the kit to evaluate the level of oxidative stress. Immunofluorescence staining was used to detect the expression of cleaved-caspase-3, the nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and the expression of heme oxygenase-1 (HO-1) in astrocytes. Western blot assay was used to detect the total Nrf2, nuclear Nrf2 and HO-1 protein levels.  
    RESULTS AND CONCLUSION: (1) Compared with the PBS control group, the astrocyte viability in the lipopolysaccharide stimulation group was reduced, and fasudil treatment improved the cell damage induced by lipopolysaccharide. (2) Compared with the PBS control group, lipopolysaccharide resulted in a significant decrease in the activity of superoxide dismutase and a significant increase in the level of malondialdehyde in astrocytes (P < 0.01). Fasudil significantly increased the activity of superoxide dismutase (P < 0.01) and reduced the level of malondialdehyde (P < 0.01). (3) Compared with the PBS control group, the expression of cleaved-caspase-3 was significantly increased in the lipopolysaccharide stimulation group. Compared with the lipopolysaccharide stimulation group, the expression of cleaved-caspase-3 was decreased in the lipopolysaccharide combined with fasudil treatment group. (4) Fasudil could promote the nuclear translocation of Nrf2 and significantly increase the expression of total Nrf2, nucleus Nrf2 and HO-1 after lipopolysaccharide stimulation. (5) The results indicate that fasudil can inhibit lipopolysaccharide-induced astrocytic injury by regulating the Nrf2/HO-1 signaling pathway.
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    Meta-analysis of autologous bone marrow mesenchymal stem cell transplantation in the treatment of ischemic stroke
    Yuan Chunhua, Cui Zhenzhen, Wu De
    2021, 25 (31):  5018-5024.  doi: 10.12307/2021.145
    Abstract ( 357 )   PDF (1207KB) ( 83 )   Save
    OBJECTIVE: Clinical trials of mesenchymal stem cell transplantation for cerebrovascular diseases have been gradually carried out in the world. However, the sample size of the studies is small, and there is lack of evidence-based medical evidence. This article is designed to systematically assess the safety and efficacy of autologous bone marrow mesenchymal stem cell transplantation in the treatment of ischemic stroke using meta-analysis.
    METHODS: Wanfang, VIP, CNKI, Cochrane Library, EMbase and PubMed databases were searched to collect clinical trials of bone marrow mesenchymal stem cell transplantation for ischemic stroke from January 2005 to May 2019. Two researchers independently performed literature screening, extraction of literature data and bias risk assessment of included literature according to inclusion and exclusion criteria, and used RevMan 5.3 software for meta-analysis.
    RESULTS:  (1) A total of 12 articles (ten were randomized controlled trials and two were non-randomized studies) with 786 ischemic stroke patients were included in the analysis. (2) Meta-analysis results showed that individual disability status (FIM score; MD=20.12, 95%CI: 3.26-36.97, P=0.02), neurological deficit (NIHSS score; MD=-2.09, 95%CI: -2.75 to -1.44, P < 0.000 01), motor function (FMA score; MD=12.24, 95%CI: 7.22-17.26, P < 0.000 01), and activities of daily living (BI score; MD=6.30, 95%CI: 5.11-7.49, P=0.005) in the autologous bone marrow mesenchymal stem cell transplantation group were superior to the control group.  
    CONCLUSION: The clinical evidence collected in the article shows that autologous bone marrow mesenchymal stem cell transplantation can effectively improve the motor function and daily living function of patients with ischemic stroke, with fewer adverse reactions. However, high-quality studies with multi-center, large-sample randomized controlled trials are required for further investigation on the clinical application of bone marrow mesenchymal stem cell transplantation.
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    In vivo track technique for mesenchymal stem cells: how to realize simultaneous tracing of distribution and survival
    Li Ye, Yang Yukun, Zhu Xiangqing, He Jie, Wang Jinxiang, Wang Yanying, Tian Chuan, Pang Rongqing, Pan Xinghua
    2021, 25 (31):  5025-5033.  doi: 10.12307/2021.146
    Abstract ( 674 )   PDF (805KB) ( 96 )   Save
    BACKGROUND: Stem cell therapy has a broad application prospect for the development of new treatment strategies for many difficult diseases. Although the number of clinical trials of stem cell therapy has increased in the past few years, due to the low immunogenicity and high proliferation ability of stem cells, there may be a potential risk of malignant transformation in vivo. The safety and effectiveness of cell therapy can be determined by imaging.
    OBJECTIVE: Detailed in vivo studies are needed to monitor the fate of transplanted cells, including their distribution, differentiation and lifespan. The development of non-invasive cell imaging techniques for real-time tracking of transplanted cells provides a powerful tool for determining the effectiveness of stem cell therapy. In this review, we summarize the advantages and disadvantages of different imaging techniques used for stem cell labeling and tracing in the last 10 years. 
    METHODS: Articles about non-invasive tracer technology of mesenchymal stem cells in PubMed database and CNKI database from January 2010 to March 2020 were searched with the English key words of “mesenchymal stem cell*, cell track*, molecular imaging” and the Chinese key words of “mesenchymal stem cells, transplantation, tracer”. The search literature types were not limited; obsolete and irrelevant studies were excluded. Finally, 92 articles were selected for review. 
    RESULTS AND CONCLUSION: At present, the molecular imaging techniques that can be used to trace stem cells in vivo mainly include optical imaging, magnetic resonance, nuclear medicine, ultrasound/photoacoustics, magnetic particle imaging, multimodal imaging and so on. The survival rate and long-term fate of mesenchymal stem cell transplantation are still in the exploratory stage. The emergence of the emergence of a variety of new multimodal contrast agents which are directly combined with indirect labeled imaging makes it possible to trace the distribution and survival of transplanted cells at the same time.
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    Possibility of in utero stem cell therapy for multiple fetal genetic diseases
    Jie Qiuling, Sun Fei
    2021, 25 (31):  5034-5039.  doi: 10.12307/2021.147
    Abstract ( 406 )   PDF (675KB) ( 62 )   Save
    BACKGROUND: The development of prenatal diagnosis and screening technology has made prenatal treatment possible. For a variety of fetal genetic diseases, in utero stem cell therapy has significant advantages.
    OBJECTIVE: To analyze the feasibility of in utero stem cell therapy in prenatal fetal diseases through the existing experimental research and clinical data.
    METHODS:  Databases of PubMed, Wanfang and CNKI were searched for the articles published from the inception to June 16, 2020. The keywords were “in utero stem cells, fetal” in English and Chinese, respectively.
    RESULTS AND CONCLUSION: With the development of prenatal diagnosis screening technology and stem cell therapy technology, in utero stem cell therapy has a significant advantage in the treatment of various fetal genetic diseases. The physiological characteristics of fetal development also provide conditions for in utero stem cell transplantation. The preclinical animal experiment research has laid the foundation for the clinical application of in utero stem cell transplantation treatment from the aspects of chimera implantation level and immune tolerance. In recent years, the development of prenatal diagnosis and screening technology, along with high-throughput molecular testing and minimally invasive surgery, can detect a variety of fetal diseases in early pregnancy, and also makes prenatal intrauterine treatment possible.
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    Mesenchymal stem cell-derived exosomes carrying miRNAs in tissue repair and treatment of related diseases: application and advantages
    Shi Qin, Sun Baolan, Yang Xiaoqing, Zhang Yuquan
    2021, 25 (31):  5040-5045.  doi: 10.12307/2021.148
    Abstract ( 378 )   PDF (742KB) ( 96 )   Save
    BACKGROUND: In recent years, increasing evidences indicate that exosomes secreted by mesenchymal stem cells (MSC-Exo) exert a repair effect on tissue and organ damage and can be used for the treatment of various diseases. MicroRNA (miRNA) is one of the most studied components in MSC-Exo. Gene editing of MSC-Exo carrying miRNA through genetic engineering and other technologies can make it a promising acellular preparation in the field of tissue engineering.
    OBJECTIVE: To review the research progress of MSC-Exo carrying miRNA in the field of tissue engineering.
    METHODS: The PubMed, Web of Science and CNKI databases were used to search by the first author for original and review articles published from January 2000 to May 2020 using the key words of “mesenchymal stem cells; exosome; micro RNA” in English and Chinese respectively. Totally 38 articles were included in analysis. 
    RESULTS AND CONCLUSION: In various systems, MSC-Exo has been shown to promote cell proliferation, inhibit apoptosis and promote angiogenesis through their miRNAs. Many preclinical studies have been carried out on the therapeutic effects of MSC-Exo and its miRNAs in cardiovascular system, digestive system, nervous system, endocrine system and immune system diseases, revealing that miRNAs exist in MSC-Exo, and their regulating role in repairing tissue damage, preventing and treating related diseases.  

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    Effect of urinary-derived stem cells and extracellular vesicles in tissue damage repair
    Cui Tianning, Liu Tao, Xiao Xiangyang, Wang Shuai, Zhang Nini, Huang Guilin
    2021, 25 (31):  5046-5052.  doi: 10.12307/2021.149
    Abstract ( 386 )   PDF (1026KB) ( 57 )   Save
    BACKGROUND: Mesenchymal stem cells and their extracellular vesicles have made great progress in promoting the repair and regeneration of tissue injury, which provides a promising clinical application for future cell-free therapeutic strategies.
    OBJECTIVE: To review the repair of urinary-derived stem cells and their extracellular vesicles in the urinary system, the skeletal system, the nervous system, as well as the problems and prospects.
    METHODS: PubMed and Wanfang databases were searched using “urine-derived stem cells, extracellular vesicles, tissue damage repair (bladder; bone; nerve tissue)” as Chinese and English search terms. The retrieve time range was from 1989 to 2020. By reading titles and abstracts for initial screening, repetitive studies and articles with irrelevant contents in English and Chinese literature were excluded. Finally, 62 articles were reviewed. 
    RESULTS AND CONCLUSION: Urine-derived stem cells are a group of cells with multi-directional differentiation potential extracted from urine, and their biological characteristics were similar to mesenchymal stem cells and embryonic stem cells. Extracellular vesicles derived from urine-derived stem cells are a kind of new cell free treatment strategy, which is currently widely used in tissue repair in the urinary system, skeletal system and nervous system. At present, it is still in the small animal experimental study; however, a large number of trials are required to confirm the safety and feasibility of tissue engineering. Thus, the urine-derived stem cells and extracellular vesicles will become a hot spot in the field of regenerative medicine.
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    Mesenchymal stem cells in the treatment of cartilage damage in osteoarthritis: role, application, and problem
    Wang Xinwei, Zhao Yingjie, Chang Yan, Wei Wei
    2021, 25 (31):  5053-5058.  doi: 10.12307/2021.150
    Abstract ( 670 )   PDF (776KB) ( 214 )   Save
    BACKGROUND: Mesenchymal stem cells have a wide range of sources and are easy to be isolated and cultured. It also has the functions of multidirectional differentiation, tissue repair, anti-inflammatory and immune regulation, which provides a new approach for the treatment of articular cartilage injury.
    OBJECTIVE: To review the application and research of mesenchymal stem cells in the treatment of osteoarthritis cartilage damage.
    METHODS: Using “osteoarthritis, cartilage damage, mesenchymal stem cell, treatment” as the English and Chinese keywords, the first author retrieved the included in PubMed and CNKI databases from 2000 to 2020. After excluding articles that were not relevant and repetitive for the purpose of the article, fifty articles were included for review in the end.  
    RESULTS AND CONCLUSION: (1) Tissue engineering methods combined the multi-differentiation function of mesenchymal stem cells with the characteristics of bioscaffold materials can better promote the repair of damaged cartilage, and has made many achievements in basic research and clinical research. (2) Joint injection of mesenchymal stem cells with the solvent can exert the therapeutic effect and expand the advantages of mesenchymal stem cells. (3) Mesenchymal stem cell exosome for the therapy of osteoarthritis cartilage damage is still in the basic stage, which will become the developmental trend of osteoarthritis cartilage damage treatment.
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    Research hotspot of seed cell selection in cartilage tissue engineering
    Liu Xiaogang, Li Tian, Zhang Duo
    2021, 25 (31):  5059-5064.  doi: 10.12307/2021.151
    Abstract ( 475 )   PDF (623KB) ( 57 )   Save
    BACKGROUND: The repair of cartilage defects such as ears, noses, throats, trachea and joints has always been one of the difficulties faced by clinical treatment. The emergence of cartilage tissue engineering has become a popular development direction for cartilage repair, in which seed cells are used to construct tissue engineered cartilage key.
    OBJECTIVE: This article intends to review the characteristics of various types of seed cells, their application in cartilage tissue engineering, and existing problems, and to bring new ideas to clinical transformation.  
    METHODS: The first author searched the relevant articles of CNKI, Wanfang, PubMed, Scopus and Web of Science databases, using “seed cells; tissue engineering; chondrocytes; stem cells; co-cultivation” as the Chinese and English search terms. Finally, 70 articles that met the criteria were selected for review.
    RESULTS AND CONCLUSION: (1) Current experimental research on cartilage tissue engineering has achieved a lot of results, but the problem of selecting seed cells is still a big problem. Chondrocytes, various types of mesenchymal stem cells, embryonic stem cells, and induced pluripotent stem cells have different degrees of advantages, but also face different challenges. (2) The discovery, development and application of various seed cells have promoted the progress of cartilage tissue engineering. Among them, the method of co-culture of chondrocytes and stem cells is currently a popular and promising seed choice for research.
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    Characteristics and effects of exosomes from different cell sources in cardioprotection
    Pu Rui, Chen Ziyang, Yuan Lingyan
    2021, 25 (31):  5065-5071.  doi: 10.12307/2021.152
    Abstract ( 507 )   PDF (688KB) ( 265 )   Save
    BACKGROUND: More and more studies have shown that exosomes have become a new direction in the diagnosis and treatment of various diseases. Exosomes play an important role in cardioprotection, but their specific mechanisms have not been fully elucidated. 
    OBJECTIVE: To summarize the diagnostic role of exosomes in cardiovascular diseases, and summarize the research on cardioprotection of exosomes from different cell sources, in order to provide a theoretical reference for better prevention and treatment of cardiovascular diseases.
    METHODS: The key words were “exosomes, cardioprotection, cardiomyocytes, endothelial cells, cardiac fibroblasts, cardiac progenitor cells, mesenchymal stem cells” in Chinese and English. The articles on various cell-derived exosomes and cardioprotection published from 1981 to 2020 were searched. According to the inclusion and exclusion criteria, 72 articles were finally included for summary and induction.
    RESULTS AND CONCLUSION: (1) Exosomes are closely related to the occurrence and development of cardiovascular diseases, and play a beneficial effect in the screening, diagnosis and prognosis of a variety of cardiovascular diseases, so exosomes can be used as potential biomarkers for the diagnosis of cardiovascular diseases. (2) Cardiomyocytes, endothelial cells, cardiac fibroblasts, cardiac progenitor cells, and mesenchymal stem cells derived exosomes mediated miRNA and related proteins play an important role in cardioprotection.
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    Action mechanism and potential function on main components of organoid culture medium
    Liu Qi, Yao Xi, Wei Zhengbo, Xie Ying
    2021, 25 (31):  5072-5078.  doi: 10.12307/2021.153
    Abstract ( 621 )   PDF (612KB) ( 263 )   Save
    BACKGROUND: Traditional 2D cell culture has become the dominant method of cell culture due to its simplicity and easy operation. However, it is doubtful because of its inability to mimic the growth mode, microenvironment, and genetic stability of cells in the host. Organoid culture highly simulates the environment in the human body and recreates certain functions of the original organs. It is currently the most reliable cell model. However, due to the complexity and variety of the culture conditions, the organoid culture conditions are not yet mature. Therefore, it is very important to summarize the existing main culture components and improve the organoid culture technology on this basis.
    OBJECTIVE: To study the main components and potential functions of various organoid culture media, providing theoretical basis for the culture of organoid establishment.
    METHODS: The first author searched the related literature published from 2009 to 2020 in PubMed database, Cochrane Library database, CNKI database, and Wanfang database using the English or Chinese keywords “organoids, cell culture, cytokines, amino acid, R-spondin-1”. After excluding those repetitive and irrelevant articles to the purpose of this review, a total of 84 eligible articles were finally selected for review. 
    RESULTS AND CONCLUSION: In addition to the basic medium, organoid culture requires the participation of cytokines, amino acids, small molecule inhibitors and other substances. Different organoid culture requires different culture conditions, which is highly related to the source of the tissue. Each component plays a vital role in development of organoids from specific tissues. This article analyzes the detail role of each main culture component by summarizing the main existing organoid culture compound, which will provide a certain reference for the stable construction of various organoid models.

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    Dental pulp fibroblasts inducing and regulating dentin-pulp regeneration
    Wei Xiaoling, Hu Weiping, Liu Mingyue, Shi Xin, Liu Jie, Gao Li, Wang Siran, Duan Yajun
    2021, 25 (31):  5079-5084.  doi: 10.12307/2021.154
    Abstract ( 361 )   PDF (656KB) ( 60 )   Save

    BACKGROUND: During pulp-dentin regeneration, other types of cells in dental pulp, such as dentin cells and stem cells, have been widely concerned and studied by scholars, while fibroblasts have been rarely studied. The study on dental pulp fibroblasts may provide a new source of cells for future pulp treatment.
    OBJECTIVE: To review the role of dental pulp fibroblasts in pulp-dentin regeneration.
    METHODS: The computer was applied to search articles on dental pulp fibroblasts and dental pulp dentine regeneration published from 2000 to 2020 inPubMed and CNKI databases. The English search terms were “pulp, fibroblast, dentin-pulp, regeneration, complement, C5a, C3a”. The Chinese search terms were “dental pulp, fibroblasts, dentin-pulp, complement, C3a, C5a”. Finally, 56 articles were summarized. 
    RESULTS AND CONCLUSION: Fibroblasts are the most abundant cells in dental pulp. Fibroblasts play an important role in regulating the immune response and function of dental pulp under normal and pathological conditions. They enable complement proteins to produce bioactive fragments, such as C3a, C5a and membrane-attack complexes, and simultaneously, through the secretion of growth factors, fine-regulate the synthesis of restorative dentin, angiogenesis and the distribution of nerve growth, which play an important role in the pulp and dentin regeneration. Therefore, in addition to odontoblasts and pulp stem cells, dental pulp fibroblasts should also be considered as an important cell in the strategy of inducing dentin-pulp regeneration.

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