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08 April 2023, Volume 27 Issue 10 Previous Issue    Next Issue

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Knockdown of NIPBL gene regulates chondrogenic differentiation of mouse bone marrow mesenchymal stem cells Ma Wenqing, Zhang Huirong, Liu Hui, Dong Lili, Yang Juandi 2023, 27 (10):  1477-1483.  doi: 10.12307/2023.288 Abstract ( 302 )   PDF (4151KB) ( 112 )   Save BACKGROUND: At present, NIPBL gene mutation has been used as the preferred indicator for the diagnosis of Cornelia de Lange syndrome. However, due to the genetic heterogeneity of the disease, clinical diagnosis and treatment are more difficult; especially, the incidence of skeletal dysplasia in children is high, and its pathogenesis is still unclear. There is currently no targeted therapy program, and the average life expectancy of children is significantly shorter than that of the general population.   OBJECTIVE: To investigate the effect of knockdown of NIPBL gene on chondrogenic differentiation ability of mouse bone marrow mesenchymal stem cells and its possible molecular regulation mechanism. METHODS:  Mouse bone marrow mesenchymal stem cells transfected with NIPBL shRNA by lentivirus were used as sh-NIPBL group, and bone marrow mesenchymal stem cells transfected with lentivirus empty vector were used as sh-NC group. Bone marrow mesenchymal stem cells without lentivirus interference were used as the blank control group. Next, the chondrogenic induction culture was carried out in the three groups. After 21 days of induction, the perimeter of the largest cross section of cartilage microspheres was measured and Alicia blue staining was used to identify the induced differentiation. The expression level of Collagen II was detected by immunofluorescence method. The expression levels of Sox-9, TGF-β1, Smad2, and Smad4 mRNA in chondrocytes were detected by real-time quantitative PCR. RESULTS AND CONCLUSION: (1) On day 21 of chondrogenic induction, the perimeter of the largest cross section of cartilage microspheres in the sh-NIPBL group was significantly smaller than that in the control group (P < 0.05). More blue intrachondral acidic mucopolysaccharides were observed in the sh-NC group than that in the sh-NIPBL group after alician blue staining under an inverted microscope. (2) After induction into chondrogenic differentiation, the expression levels of Collagen II and Sox-9 in bone marrow mesenchymal stem cells of the sh-NIPBL group were lower than those in the sh-NC and blank control groups (P < 0.05). (3) In the process of chondrogenic induction, the expression levels of TGF-β1, Smad2, and Smad4 mRNA of the sh-NIPBL group were lower than those in the sh-NC and blank control groups (P < 0.05). (4) These findings suggest that lentiviral knockdown of NIPBL gene expression reduced the chondrogenic differentiation of bone marrow mesenchymal stem cells, and this process was mediated by the TGF-β1/Smad signaling pathway. Figures and Tables | References | Related Articles | Metrics

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Memory effect of bone marrow mesenchymal stem cells on osteogenesis after mechanical stimulation Chen Chunxiao, Jiang Letao, Shen Yue, Yan Jiakai, Li Ke, Shi Yu, Lin Wenzheng, Li Hanwen, Chen Hao 2023, 27 (10):  1501-1506.  doi: 10.12307/2023.290 Abstract ( 449 )   PDF (2043KB) ( 88 )   Save BACKGROUND: Bone marrow mesenchymal stem cells are ideal seed cells for tissue engineering, and mechanical stimulation can guide their differentiation. It has been found that stem cells have mechanical memory, that is, the change induced by mechanical stimulation may affect the long-term fate of stem cells.   OBJECTIVE: To investigate the memory effect of bone marrow mesenchymal stem cells on mechanical stimulation and to analyze the epigenetic mechanism. METHODS:  (1) Mouse bone marrow mesenchymal stem cells were isolated, and the differentiation ability of the three-lineage was detected for further use at passage 3. (2) Mouse bone marrow mesenchymal stem cells were stimulated using extensometer in vitro to detect osteogenic differentiation before and after stretching. (3) The stemness of cells after stretching was detected by flow cytometry. (4) The stretched and unstretched cells were re-digested into ordinary 12-well plates and cultured for 14 days to detect the osteogenic differentiation of the cells. (5) Immunofluorescence staining was used to detect and screen the key histone modification changes that cause the mechanical memory of stem cells, and to preliminarily clarify the possible mechanism of epigenetic regulation.   RESULTS AND CONCLUSION: (1) Mechanical stimulation of 5% deformation, 0.5 Hz, 6 hours per day for 7 days could induce the differentiation of mouse bone marrow mesenchymal stem cells to osteogenic direction. (2) After reseeding plate culture, the stretched cells remained dry and continued to differentiate toward osteogenesis. (3) The results showed that bone marrow mesenchymal stem cells had epigenetic memory for mechanical stimulation, and this epigenetic memory may be related to histone H3K4me3 modification, which is induced by mechanical stimulation. Figures and Tables | References | Related Articles | Metrics

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Effect of a disintegrin and metalloproteases 10 on proliferation and osteogenic differentiation of bone marrow mesenchymal stem cells induced by steroid-induced osteonecrosis of femoral head Fan Jun, Wu Chenhuan, Cheng Zhonghua 2023, 27 (10):  1507-1513.  doi: 10.12307/2023.369 Abstract ( 404 )   PDF (2418KB) ( 90 )   Save BACKGROUND: Many studies have found that the pathological progression of steroid-induced osteonecrosis of the femoral head is related to abnormal proliferation and osteogenic differentiation of bone marrow mesenchymal stem cells, in which a disintegrin and metalloproteases 10 (ADAM10) is highly involved, but the specific mechanism remains unclear.   OBJECTIVE: To investigate the effects of ADAM10 on proliferation and osteogenic differentiation of bone marrow mesenchymal stem cells derived from steroid-induced osteonecrosis of the femoral head patients and its possible mechanism. METHODS:  Bone marrow was harvested from proximal femur in 23 patients with steroid-induced osteonecrosis of the femoral head and 17 patients with femoral neck fracture under sterile conditions. Bone marrow mesenchymal stem cells from steroid-induced osteonecrosis of the femoral head (S-BMSCs) and femoral neck fracture (F-BMSCs) were isolated by density gradient centrifugation, and cultured to the third generation in vitro. The proliferation activity of cells in the two groups was detected by CCK-8 assay. Alizarin red staining and alkaline phosphatase staining were used to observe the osteogenic differentiation ability of cells in the two groups. qRT-PCR and western blot assay were used to detect the levels of ADAM10 mRNA and protein in cells of the two groups. S-BMSCs were infected with ADAM10 overexpression lentivirus vector, and then treated with Notch signaling pathway inhibitor DAPT. The proliferation activity of these cells was detected by CCK-8 assay. Alizarin red staining and alkaline phosphatase staining were used to observe the osteogenic differentiation of cells. qRT-PCR was used to detect the expression levels of osteogenic markers alkaline phosphatase, Runt-related transcription factor 2, and osteocalcin mRNA. The expression levels of Notch signaling pathway related proteins Notch1, NICD, and Hes1 were detected by western blot assay.   RESULTS AND CONCLUSION: (1) The proliferation activity, osteogenic differentiation ability and the expression level of ADAM10 in S-BMSCs were significantly lower than those in F-BMSCs (P < 0.01). (2) After ADAM10 overexpression, the proliferation activity, osteogenic differentiation ability, the expression levels of alkaline phosphatase, Runt-related transcription factor 2, and osteocalcin mRNA and Notch1, NICD and Hes1 protein of S-BMSCs were significantly increased (P < 0.05). However, combined intervention with DAPT significantly inhibited the promoting effects of ADAM10 overexpression on proliferation activity and osteogenic differentiation ability of S-BMSCs, and inhibited the activation of Notch signaling pathway. (3) The results show that ADAM10 can be underexpressed in S-BMSCs, and its overexpression can enhance the proliferation and osteogenic differentiation ability of S-BMSCs, and its mechanism may be related to the activation of Notch signaling pathway. Figures and Tables | References | Related Articles | Metrics

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Lentiviral down-regulation of casein kinase 2-interacting protein-1 expression in bone marrow mesenchymal stem cells to repair alveolar bone defects in osteoporosis rats Xie Mengsheng, Long Yanming, Li Xiaojie 2023, 27 (10):  1528-1533.  doi: 10.12307/2023.247 Abstract ( 326 )   PDF (8714KB) ( 17 )   Save BACKGROUND: Osteoporosis is a frequently encountered and urgent problem in the clinical repair and treatment of alveolar bone and often affects the treatment effect. Casein kinase 2-interacting protein-1 (CKIP-1) has recently been found to have a negative regulation of osteogenesis, so it is promising as a new target for the treatment of osteoporosis. OBJECTIVE: To explore the repair effect of bone marrow mesenchymal stem cells modified with CKIP-1 on alveolar bone defects in osteoporosis rats.  METHODS:  (1) Bone marrow mesenchymal stem cells were isolated and cultured from 1-week-old SD rats. Lentiviral transfection reduced the expression of CKIP-1 in bone marrow mesenchymal stem cells. (2) The model of osteoporosis rats was established by intragastric administration of retinoic acid (70 mg/kg per day) for 21 days. The complex of bone marrow mesenchymal stem cells modified with CKIP-1 and gelatin sponge, the complex of bone marrow mesenchymal stem cells transfected with empty vector and gelatin sponge, and the gelatin sponge were implanted into the alveolar bone defect of the osteoporosis rat model, separately. Gelatin sponge was implanted into bilateral alveolar bone defects of normal rat model of the normal group. After 30 days of normal feeding, the maxillary alveolar bone was taken for sectioning and staining, and the healing of bone defect was calculated by the Lane-Sandhu histological score and the percentage of new bone. The relative mRNA expression and positive expression of CKIP-1, alkaline phosphatase and osteocalcin in the alveolar bone of each group were detected by qRT-PCR and immunohistochemical staining.  RESULTS AND CONCLUSION: (1) Compared with empty vector transfection, the relative expression of CKIP-1 mRNA in bone marrow mesenchymal stem cells modified with CKIP-1 decreased (P < 0.05). (2) Compared with the bone marrow mesenchymal stem cells transfected with the empty vector and gelatin sponge complex group and the gelatin sponge group, the Lane-Sandhu histological score and the percentage of new bone significantly increased in the bone marrow mesenchymal stem cells modified with CKIP-1 and gelatin sponge complex group (P < 0.05), which were similar to the normal group; the expression levels of alkaline phosphatase and osteocalcin were significantly increased (P < 0.05). (3) The results indicated that local transplantation of CKIP-1 transfected modified bone marrow mesenchymal stem cells had better repair effect on alveolar bone defects in osteoporosis rats. Figures and Tables | References | Related Articles | Metrics

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TLN1 negatively regulates adipogenic differentiation of bone marrow mesenchymal stem cells through activating the beta-catenin signaling pathway Huang Hongyan, Ke Haoteng, Ye Weijia, Deng Huazong, Wang Tao, Cai Mingxi, Chen Qifan, Cen Shuizhong 2023, 27 (10):  1578-1583.  doi: 10.12307/2023.319 Abstract ( 321 )   PDF (3105KB) ( 98 )   Save BACKGROUND: The balance between osteogenic and adipogenic differentiation in bone marrow mesenchymal stem cells plays a key role in bone metabolic diseases. Our previous study confirmed that TLN1 can regulate osteogenic differentiation of bone marrow mesenchymal stem cells, but its effect on adipogenic differentiation of bone marrow mesenchymal stem cells remains unclear.  OBJECTIVE: To investigate the role and mechanism of TLN1 in the adipogenic differentiation of bone marrow mesenchymal stem cells.  METHODS:  Bone marrow mesenchymal stem cells were induced to adipogenic differentiation and TLN1 expression was detected by qRT-PCR and western blot assay. CCK-8 was used to detect the proliferation of bone marrow mesenchymal stem cells after TLN1 knockdown. The Oil red O staining and quantification were performed after adipogenic induction. Besides, qRT-PCR was used to detect the gene expression levels of the key molecules of adipogenic differentiation of bone marrow mesenchymal stem cells including PPAR-γ and C/EBP-α. Western blot assay was used to detect the classic pathway of adipogenesis. Meanwhile, TLN1 was knockdown and β-catenin activator was added to detect the adipogenic differentiation of bone marrow mesenchymal stem cells, to explore the specific molecular mechanism of TLN1 regulating adipogenesis.  RESULTS AND CONCLUSION: TLN1 expression was down-regulated during adipogenic differentiation of bone marrow mesenchymal stem cells. TLN1 knockdown had no significant effect on the proliferation of bone marrow mesenchymal stem cells, but significantly increased the adipogenic induction of bone marrow mesenchymal stem cells. TLN1 knockdown could inhibit the expression of active β-catenin, while activation of β-catenin signaling pathway could reverse the enhancement of adipogenesis mediated by TLN1 knockdown. These findings suggest that TLN1 expression is gradually down-regulated during the adipogenic differentiation of bone marrow mesenchymal stem cells, and TLN1 knockdown can promote the adipogenic differentiation of bone marrow mesenchymal stem cells by inhibiting β-catenin signaling pathway. Figures and Tables | References | Related Articles | Metrics

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Effect of adipose-derived stem cells stimulated by direct current electric field on refractory wound healing in diabetic rats Zhang Rui, Liu Lan, Xie Defu, Lin Yingxi, Ren Hongjing, Yan Hong 2023, 27 (10):  1484-1491.  doi: 10.12307/2023.268 Abstract ( 398 )   PDF (5977KB) ( 196 )   Save BACKGROUND: Adipose-derived stem cells have a great potential in wound healing and regeneration and we have proven that a direct-current electric-field can promote the proliferation of human adipose-derived stem cells without changing biological characteristics.   OBJECTIVE: To investigate the effect of rat adipose-derived stem cells stimulated by a direct-current electric-field on refractory wound healing in diabetic rats. METHODS:  (1) Rat adipose-derived stem cells were obtained. After identification, they were pretreated with 100 mV/mm or 0 mV/mm of direct-current electric-field stimulation, with a frequency of 1 h/d, for 3 days. (2) Diabetic refractory wound models were constructed and randomly divided into three groups, with 7 rats in each group, totaling 21 rats. Animals in the electric-field-rat adipose-derived stem cell and rat adipose-derived stem cell groups were injected with 1 mL of electric-field-rat adipose-derived stem cells or normal rat adipose-derived stem cells, respectively, at multiple points of the wound, with a cell concentration of 1×109 cells/L. The PBS group was given the same amount of PBS. (3) At 3, 7, and 14 days after model establishment, the degree of wound healing was observed. Laser speckle contrast imaging was used to record the blood perfusion of rat wounds. The histological changes of wound healing were evaluated by hematoxylin and eosin staining. Microvessels were counted. The expression of vascular endothelial growth factor in the wound tissue was observed by immunohistochemistry. The expression of CD31 was observed by immunofluorescence.   RESULTS AND CONCLUSION: (1) Compared the normal rat adipose-derived stem cells and PBS groups, wounds in the electric-field-rat adipose-derived stem cell group were nearly completely healed on day 14, and the wound-healing speed was significantly accelerated (P < 0.05). (2) In the electric-field-rat adipose-derived stem cell group, wound epithelization began on day 3. On day 14, the epidermal structure was more complete and continuous in the electric-field-rat adipose-derived stem cell group than those of the other two groups; moreover, the wound angiogenesis was increased (P < 0.05) and the expression levels of vascular endothelial growth factor and CD31 were significantly greater (P < 0.05). (3) The wound blood perfusion of the three groups gradually reached a peak and retreated with the progression of time. The blood perfusion of the electric-field-rat adipose-derived stem cell group was significantly higher than that of the PBS group at different time points after treatment (P < 0.05) and was significantly higher than that of the normal rat adipose-derived stem cell group on day 7 (P < 0.05). (4) The results showed that rat adipose-derived stem cells stimulated by direct-current electric-field exposure could accelerate the healing process of diabetic refractory wounds. The potential mechanism here may be related to the ability of rat adipose-derived stem cells to increase blood perfusion, promote vascular endothelial growth factor expression, and increase the rate of angiogenesis, which provides a new idea for culturing adipose-derived stem cells in vitro and accelerating the actual clinical transformation. Figures and Tables | References | Related Articles | Metrics

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Effects of multiple myeloma cell conditioned medium on proliferation and differentiation of human umbilical cord mesenchymal stem cells Yang Xu, Wang Feiqing, Zhao Jianing, Zhang Chike, Liang Huiling, Qi Shasha, Wu Dan, Liu Yanqing, Tang Dongxin, Liu Yang, Li Yanju 2023, 27 (10):  1514-1520.  doi: 10.12307/2023.287 Abstract ( 359 )   PDF (6937KB) ( 93 )   Save BACKGROUND: In recent years, the interaction between stem cells and tumor in tumor microenvironment has become a hot topic. While few studies have reported the experiments of human umbilical cord mesenchymal stem cells in conditioned culture medium of human multiple myeloma cells.   OBJECTIVE: To investigate the effects of conditioned medium of human multiple myeloma cells on proliferation, migration and differentiation of human umbilical cord mesenchymal stem cells. METHODS:  Human umbilical cord mesenchymal stem cells were extracted by tissue block adherent method. At the same time, the supernatant of human multiple myeloma RPMI8226 and U266 cells was cultured and extracted to prepare conditioned culture medium. The cells were grouped according to different media: the control group was only cultured with L-DMEM complete culture medium. In experimental group, human umbilical cord mesenchymal stem cells were cultured with 20% RPMI8226 cell conditioned medium or 20% U266 cell conditioned medium and 80% L-DMEM complete medium. After 24 hours of culture, the proliferation of cells was analyzed by CCK8 assay, EDU, and crystal violet staining. The migration of cells was evaluated by the scrape method. Osteogenic and adipogenic induction experiments were used to detect cell differentiation. Real-time PCR was used to detect the mRNA expressions of cyclin genes p16 and p21 in cells.   RESULTS AND CONCLUSION: The proliferation of cells in the experimental group was more than that in the control group (P < 0.05); the migration rate was higher than that in the control group (P < 0.05); the staining area of mineralized nodules was smaller than that of the control group (P < 0.05); and the positive staining area of lipid droplets was larger than that of the control group (P < 0.05); the mRNA expression of cell cycle genes p16 and p21 in the experimental group was lower than that in the control group (P < 0.05). These findings exhibit that conditioned culture medium of human multiple myeloma cells can promote the proliferation, migration, and adipogenic differentiation of human umbilical cord mesenchymal stem cells, and inhibit osteogenic differentiation. This may be associated with the inhibition of p16 and p21 gene expression. Figures and Tables | References | Related Articles | Metrics

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Therapeutic effect of umbilical cord mesenchymal stem cells modified by miR-1-5p in MRL/lpr lupus mice Ding Lili, Hu Mingzhi, Wu Zhihui, Sun Xiaolin, Wang Yongfu 2023, 27 (10):  1492-1500.  doi: 10.12307/2023.270 Abstract ( 306 )   PDF (6681KB) ( 81 )   Save BACKGROUND: Numerous studies have shown that mesenchymal stem cells can treat autoimmune diseases through a variety of immunomodulatory pathways, and genetic modification may improve the therapeutic potential of mesenchymal stem cells. MiR-1-5p is lowly expressed in systemic lupus erythematosus, and mesenchymal stem cells overexpressing miR-1-5p may have a therapeutic effect on systemic lupus erythematosus.   OBJECTIVE: To investigate whether miR-1-5p-modified umbilical cord mesenchymal stem cells mediate the JAK2/STAT3 pathway and have a therapeutic effect on systemic lupus erythematosus MRL/lpr model mice. METHODS:  Twenty MRL/lpr lupus mice were randomly divided into miR-1-5p transfected umbilical cord mesenchymal stem cells treatment group (UC-MSCs+miR-1-5p group), miRNA negative control transfected umbilical cord mesenchymal stem cells treatment group (UC-MSCs+miR-NC group), umbilical cord mesenchymal stem cell treatment group (UC-MSCs group), PBS treatment group (PBS group), and MRL/lpr lupus mice untreated (control group). MRL/lpr lupus mice were treated with tail vein transplantation, once a week, 5 times. Mice were sacrificed at 1-week intervals after the end of treatment. Hematoxylin-eosin staining was used to observe the pathological changes of liver tissue and intestinal tissue of MRL/lpr mice in each group. Western blot assay was used to detect JAK2/STAT3 pathway proteins and their phosphorylation levels and expression levels of interleukin-18 in kidney tissue of mice in each group.   RESULTS AND CONCLUSION: (1) Compared with control group, the infiltration of inflammatory cells in liver tissue of MRL/lpr mice in UC-MSCs+miR-1-5p group, UC-MSCs+miR-NC group, and UC-MSCs group decreased significantly, and hepatocyte edema and degeneration could be seen in UC-MSCs+miR-NC group. Goblet cells in intestinal tissue of MRL/lpr mice in UC-MSCs+miR-1-5p group increased significantly, but there was no significant difference among other groups. (2) Compared with control group, the expression of p-JAK2 (Y1007+Y1008), p-STAT3 (s727) and interleukin-18 in renal tissue of lupus mice in UC-MSCs+miR-1-5p group was significantly down-regulated (P < 0.05); p-STAT3(s727) (P < 0.05) and interleukin-18 (P < 0.01) were significantly down-regulated in the kidney tissue of lupus mice in UC-MSCs group; expression level of interleukin-18 in UC-MSCs+miR-NC group was significantly down-regulated (P < 0.05); and there was no significant difference in the expression of p-STAT3 (Y705) in renal tissue of lupus mice of each group (P > 0.05). The expression of interleukin-18 in UC-MSCs group was significantly lower than that in PBS group (P < 0.05). (3) The results suggested that umbilical cord mesenchymal stem cells modified by miR-1-5p may alleviate liver and intestinal damage in MRL/lpr mice by inhibiting the activation of JAK2/STAT3 pathway and the expression of interleukin 18, thereby playing a certain therapeutic role in lupus mice. Figures and Tables | References | Related Articles | Metrics

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Efficient expansion of natural killer cells from cryopreserved umbilical cord blood by pure cytokine method without animal ingredients Diao Xiaojuan, Shi Chaoqun, Li Dong, Wang Shuai, Xiao Chun, Liu Guojun, Qu Tingyu, Yang Weijuan, Jia Xiaopeng 2023, 27 (10):  1572-1577.  doi: 10.12307/2023.318 Abstract ( 390 )   PDF (2178KB) ( 134 )   Save BACKGROUND: To obtain a large number of high purity trophoblast-free, animal-derived natural killer (NK) cells from deep cryopreserved cord blood for better experimental studies on tumor killing by NK cells, a safe and efficient method for expanding and culturing NK cells in vitro was obtained by using NK expansion culture kits and serum substitutes. OBJECTIVE: To establish a technical system for the expansion of NK cells from frozen cord blood using pure cytokines, and demonstrate their tumor-killing ability in vitro. METHODS:  The frozen cord blood stored in liquid nitrogen was thawed to optimize the recovery system. The individual nucleated cells were collected by Ficoll density gradient centrifugation and inoculated in pre-plated T175 culture flasks. Cells were cultured using the cytokine + serum replacement method for 21 days and counted. The ratio of CD3-CD56+ in cells was detected by flow cytometry. The data obtained were compared with the data of K562 trophoblast cells + fetal bovine serum culture method. Meanwhile, myeloid leukemia cells K562 were used as target cells, and CCK-8 kit was used to perform different potent target ratios of NK cells to kill K562 cells. Later, simulated storage transport experiments were performed for 12 hours. The changes in the ratio of CD3-CD56+ were detected by flow cytometry and the apoptosis ratio was determined using Annexin V/PI double-staining method.  RESULTS AND CONCLUSION: (1) The cells were expanded and cultured for 14 days using K562 trophoblast cells + fetal bovine serum, and the cells expanded (51.47±4.28) fold. After 21 days of expansion culture using cytokine + serum substitute method, the number of cells was more than 5×109; the cells expanded (328.32±116.36) times; the cell expansion ploidy was significantly higher; the CD3-CD56+ purity ratio obtained by both methods was above 80%; no significant difference was seen. (2) The killing effect of NK cells cultured by pure cytokine method on K562 cells (effective target ratio=10:1) was more than 80%. (3) The ratio of CD3-CD56+ did not change significantly during the 12-hour simulated storage experiment until the 12 hours, when the apoptosis rate of NK cells was < 7%. (4) The results showed that the optimized recovery system and pure factor expansion method can efficiently culture high-purity NK cells with the ability to effectively kill K562 tumor cells, and still have good cell purity and low apoptosis rate after 12-hour storage and transportation. Figures and Tables | References | Related Articles | Metrics

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Gingiva-derived mesenchymal stem cells in repair of traumatic oral ulcer Zhao Liru, Xu Shukui, Wu Yifan, Luo Yaxian, Shang Linlin, Li Wenwen, Ma Wensheng 2023, 27 (10):  1541-1546.  doi: 10.12307/2023.300 Abstract ( 534 )   PDF (2818KB) ( 160 )   Save BACKGROUND: Gingiva-derived mesenchymal stem cells can promote the wound healing of skin tissue. However, it has not been clearly reported whether it has a potential therapeutic effect on oral ulcers.   OBJECTIVE: To study the therapeutic potential of gingiva-derived mesenchymal stem cells in traumatic oral ulcer. METHODS:  The animal models of oral ulcer in 21 SD rats were established by mechanical combined with chemical method. They were randomly divided into two groups: ulcer group containing 11 rat, and gingiva-derived mesenchymal stem cell group containing 10 rats. A total of 1×106 gingiva-derived mesenchymal stem cells were injected at ulcer center and surrounding area in every rat of gingiva-derived mesenchymal stem cell group at 2 days after model establishment. The rats in ulcer group were injected with the same amount of PBS. Only one rat in ulcer group was executed one day after modeling to observe the formation of ulcer. The other rats were executed 3 and 7 days after modeling, 5 rats in each group at different time points. Ulcer healing was observed by gross observation and histology.   RESULTS AND CONCLUSION: (1) Gingiva-derived mesenchymal stem cells cultured in vitro showed spindle-like structure, similar to fibroblasts, presenting full cell body with osteogenic and adipogenic differentiation potential. (2) The model of oral ulcer could be successfully established by mechanical combined with chemical method. During natural healing of ulcer group, the inflammatory reaction of the ulcer reached its most severe on day 3. On day 7, the ulcer showed a healing trend, but had not achieved completely healing. (3) On day 3 after modeling, the inflammatory response of the ulcer group was stronger than that of the gingiva-derived mesenchymal stem cell group. On day 7, the ulcer wound in the gingiva-derived mesenchymal stem cell group had achieved basically healing. (4) The hematoxylin-eosin staining showed the formation of thin epithelium at the ulcer in the gingiva-derived mesenchymal stem cell group on day 7. Masson staining results showed that the collagen formation in the gingiva-derived mesenchymal stem cell group was thicker and more regular than that in the ulcer group on day 7 after modeling. (5) These results suggest that gingiva-derived mesenchymal stem cells can reduce the inflammatory response in the early stage of traumatic oral ulcer in rats and promote the healing process of oral ulcer. The formation time of the oral epithelium is earlier, and the collagen formation is thicker and the arrangement is more regular. Figures and Tables | References | Related Articles | Metrics

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Effect of macrophage inflammatory protein-1 alpha on the biological behavior of human periodontal ligament stem cells Wang Zhaoxin, Nijati•Tursun, Dai Huijuan, Wang Junxiang, Xiaheida•Yilaljiang, Li Shuhui 2023, 27 (10):  1521-1527.  doi: 10.12307/2023.284 Abstract ( 460 )   PDF (2272KB) ( 132 )   Save BACKGROUND: A large number of studies focus on the effect of inflammatory factors on human periodontal ligament stem cells; however, there are few reports on the expression of chemokine macrophage inflammatory protein-1α in human periodontal ligament stem cells at home and abroad.   OBJECTIVE: To investigate the effects of different mass concentrations of macrophage inflammatory protein 1α on the proliferation, apoptosis, and migration of human periodontal ligament stem cells and the correlation of Notch signaling pathway. METHODS:  Healthy orthodontic reduced premolars were extracted from patients aged 12-25 years (all signed informed consent), and human periodontal ligament stem cells were isolated and cultured by tissue block method combined with enzymatic digestion. Passage 3 human periodontal ligament stem cells at logarithmic growth stage were divided into control group, 1, 10, 100 mg/L macrophage inflammatory protein-1α groups. Cell proliferation was detected by CCK-8 assay at 1, 3, 5, and 7 days. At 48 hours, the apoptotic ability of each group was detected by flow cytometry. Cell migration ability of each group was detected by Transwell chamber test. ELISA was used to detect the level of secreted tumor necrosis factor α. qRT-PCR and western blot assay were used to detect the mRNA and protein expression levels of Notch1 and Hes1.   RESULTS AND CONCLUSION: (1) 1 mg/L macrophage inflammatory protein-1α had no significant effect on the biological behavior of human periodontal ligament stem cells. 10 mg/L macrophage inflammatory protein-1α significantly promoted the proliferation and migration of human periodontal ligament stem cells, and 100 mg/L macrophage inflammatory protein-1α significantly promoted the apoptosis of human periodontal ligament stem cells, inhibited the proliferation and migration of human periodontal ligament stem cells. (2) 1 mg/L macrophage inflammatory protein-1α had no significant effect on the expression of Notch1 and Hes1 proteins in human periodontal ligament stem cells. 10 mg/L macrophage inflammatory protein-1α had no significant effect on the expression of Notch1 protein in human periodontal ligament stem cells, but could down-regulate the expression level of Hes1 protein in the cells. 100 mg/L macrophage inflammatory protein-1α could up-regulate the expression of Notch1 and Hes1 protein in cells. (3) The level of tumor necrosis factor α secreted by  human periodontal ligament stem cells of the 1 mg/L macrophage inflammatory protein-1α group was not significantly different from that of the control group. 10 mg/L macrophage inflammatory protein-1α promoted the secretion of tumor necrosis factor α; 100 mg/L macrophage inflammatory protein-1α inhibited the secretion of tumor necrosis factor α. (4) These results exhibited that 10 mg/L macrophage inflammatory protein-1α promoted the proliferation, migration and tumor necrosis factor α secretion of human periodontal ligament stem cells, and the mechanism might be related to the down-regulation of Notch signaling pathway. 100 mg/L macrophage inflammatory protein-1α inhibited the proliferation and migration of human periodontal ligament stem cells and the secretion of tumor necrosis factor α, and promoted the apoptosis of human periodontal ligament stem cells. The mechanism may be related to the up-regulation of Notch signaling pathway. Figures and Tables | References | Related Articles | Metrics

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Platelet-derived growth factor BB promotes proliferation and osteogenic differentiation of human periodontal ligament stem cells Chen Jiana, Nie Minhai, Hu Xinyue, Liu Xuqian 2023, 27 (10):  1534-1540.  doi: 10.12307/2023.289 Abstract ( 361 )   PDF (3368KB) ( 166 )   Save BACKGROUND: Human periodontal ligament stem cells have the potential for multidirectional differentiation. Under certain conditions, they can differentiate towards osteogenesis and induce bone tissue regeneration. Therefore, human periodontal ligament stem cells, as one of bone tissue engineering seed cells, have good research prospects and clinical application value in bone regeneration and repair of alveolar bone defects caused by periodontal disease.   OBJECTIVE: To explore the functional characteristics of platelet derived growth factor-BB in promoting the proliferation and osteogenic differentiation of human periodontal ligament stem cells, aiming to provide relevant laboratory evidence for bone regeneration and repair of alveolar bone defects. METHODS:  Human periodontal ligament stem cells were taken from the periodontal ligament tissue of orthodontic extraction patients in the Department of Oral and Maxillofacial Surgery, Affiliated Stomatology Hospital of Southwest Medical University. The growth curve of passages 1-6 human periodontal ligament stem cells and the proliferation curve of human periodontal ligament stem cells under the action of different concentrations of platelet-derived growth factor BB were drawn by CCK-8 assay. Passage 3 human periodontal ligament stem cells were divided into blank control group, osteoinduction liquid group, osteoinduction liquid + platelet-derived growth factor BB group. The formation of mineralized nodules after induction for 7, 14, and 21 days was observed by mineralized experiment. RT-qPCR and western blot assay were used to detect the relative expression of Runx2 and bone morphogenetic protein 2 mRNA and protein.   RESULTS AND CONCLUSION: (1) CCK-8 assay results showed that the passages 2 and 3 human periodontal ligament stem cells in logarithmic growth phase were significantly higher than that of the other passages (P < 0.05). (2) At the same time point, the proliferation of human periodontal ligament stem cells in 100 μg/L platelet-derived growth factor BB group was significantly better than that in 0, 50, 200 μg/L platelet-derived growth factor BB group (P < 0.05). (3) 100 μg/L platelet-derived growth factor BB combined with osteoinduction liquid had an obvious osteogenic induction effect on human periodontal ligament stem cells. On day 14 of osteogenic induction, compared with the osteoinduction liquid group and the blank control group, mRNA and protein expression levels of Runx2 and bone morphogenetic protein 2 were significantly increased in the osteoinduction liquid + platelet-derived growth factor BB group (P < 0.05). (4) These resuls indicate that platelet-derived growth factor BB can promote the proliferation and osteogenic differentiation of human periodontal ligament stem cells. Figures and Tables | References | Related Articles | Metrics

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Establishment and identification of an efficient protocol for differentiation of endothelial cells from human induced pluripotent stem cells Huang Wenjun, Wang Jie, Zhou Yafei, Li Huan, Jiang Congshan, Zhang Yanmin, Zhou Rui 2023, 27 (10):  1553-1559.  doi: 10.12307/2023.340 Abstract ( 441 )   PDF (3426KB) ( 32 )   Save BACKGROUND: Similar to the human induced embryonic stem cells, human induced pluripotent stem cell is a kind of pluripotent stem cells. By virtue of the differentiation potential of three germ layers and self-renewal ability, it could serve as a means to generate a scalable source of cells for therapeutic applications. OBJECTIVE: To establish a protocol for the directed differentiation of human induced pluripotent stem cells into functional endothelial cells. METHODS:  The authenticity of human induced pluripotent stem cells was verified by the immunofluorescence method. Human induced pluripotent stem cells were then differentiated into cardiac mesoderm, endothelial progenitor cells and finally functional endothelial cells through the manipulation of signaling pathways using recombinant transcription factors and small molecule compounds by adding activin A, GSK pathway inhibitor CHIR99021/bone morphogenetic protein 4, fibroblast growth factor/vascular endothelial growth factor/bone morphogenetic protein 4, basic fibroblast growth factor/vascular endothelial growth factor/CHIR99021 on days 0, 1, 2, and 5 sequentially. The induced endothelial cells were characterized by the morphology and the expression of endothelial cells-specific markers using brightfield microscope, real-time quantitative PCR and immunofluorescence method. Moreover, the tube formation assay was performed to test the angiogenetic ability of induced endothelial cells.  RESULTS AND CONCLUSION: (1) The human induced pluripotent stem cells expressed high-levels of the induced pluripotent stem cell-specific markers (OCT4, NANOG, and SSEA4) and self-renewal marker (Ki67) as well. (2) The human induced pluripotent stem cells were successfully induced sequentially into to cardiac mesoderm cells, endothelial progenitor cells and final typical endothelial cells. (3) Real-time quantitative PCR results showed that with the progression of the differentiation, endothelial progenitor cell markers (KDR and CD34) were increased, and then gradually decreased; and endothelial cell markers (VE-CADHERIN, ICAM1 and PECAM1) were gradually increased. Immunofluorescence at the protein level further confirmed the increasing trend of endothelial cell marker expression. (4) Tube formation assay showed that the number of endothelial cells-generated blood vessels increased with the increase of the concentration of vascular endothelial growth factor. (5) It is concluded that an experimental protocol for the directed differentiation of human induced pluripotent stem cells into endothelial cells has been successfully established, which is expected to provide a cellular basis and experimental basis for future blood vessel construction. Figures and Tables | References | Related Articles | Metrics

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Effects of high mobility group box 1 and ERK1/2 pathway on autophagy of human periodontal ligament cells under tensile stress Zhang Min, Bai Shulin, Li Shenghong, Fan Zhibo, Xie Yijia, Xu Xiaomei 2023, 27 (10):  1560-1566.  doi: 10.12307/2023.302 Abstract ( 370 )   PDF (3546KB) ( 151 )   Save BACKGROUND: The mechanical force signal transduction pathway and its regulation mechanism of bone remodeling after orthodontic tooth movement are hot topics in orthodontic biomechanics and biology. In the present study, the mechanism of complex molecular signal network in the response of periodontal ligament cells to mechanical stimulation during orthodontic tooth movement is not clear.   OBJECTIVE: To investigate the effect of high mobility group box 1 (HMGB1) and ERK1/2 pathway on autophagy in human periodontal ligament cells under tensile stress during orthodontic tooth movement. METHODS:  The passages 3-5 human periodontal ligament cells were selected and the HMGB1 distribution in the cells was observed by immunofluorescence under cyclic tensile stress. The expression levels of autophagy-associated protein LC3-II, Beclin-1 and HMGB1 were detected by real-time fluorescence quantitative PCR (RT-qPCR) and western blot assay. After tensile stress loading, nuclear and cytoplasmic proteins were extracted respectively. Western blot assay was used to detect HMGB1 protein level in nucleus and cytoplasm. The mechanisms by which HMGBI participated in regulating autophagy were investigated. Cellular autophagy levels were measured by immunofluorescence, RT-qPCR and western blot assay using ethyl pyruvate, a cytosolic inhibitor of HMGB1. Finally, PD98059 was used to inhibit ERK1/2 pathway, and the autophagy level of HMGB1 was detected by RT-qPCR and western blot assay. The mechanism of HMGB1 regulating autophagy through ERK1/2 pathway was explored.   RESULTS AND CONCLUSION: (1) By external tensile stress loading, the autophagy level and HMGB1 expression of human periodontal ligament cells were increased and HMGB1 translocated from nucleus to cytoplasm. (2) Human periodontal ligament cells participated in the regulation of autophagy induced by tensile stress through HMGB1 nuclear-cytoplasmic translocation. (3) PD98059, an inhibitor of the ERK1/2 pathway, significantly inhibited the autophagy induced by HMGB1 under tensile stress. (4) These findings suggested that under tensile stress, HMGB1 transferred from the nucleus to the cytoplasm, and regulated autophagy by ERK12 pathway to maintain the homeostasis of human periodontal ligament cells and periodontal dynamic equilibrium. Figures and Tables | References | Related Articles | Metrics

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Schwann cell-derived exosomes attenuate angiogenesis and fibrotic scar formation and promote nerve repair Li Xialin, Hu Guangxun, Pan Dayu 2023, 27 (10):  1567-1571.  doi: 10.12307/2023.363 Abstract ( 319 )   PDF (2790KB) ( 144 )   Save BACKGROUND: Spinal cord injury can result in severe damage to axons and neuronal death, leading to permanent loss of motor and/or sensory function. At present, the treatment methods for spinal cord injury are still very limited. As a non-cellular therapy, exosomes have attracted much attention due to their powerful biological activities, and have the potential to become an emerging treatment option for spinal cord injury.  OBJECTIVE: To investigate the role of Schwann cell-derived exosomes on nerve axons after spinal cord injury in mice.  METHODS: Thirty C57 mice were randomly divided into sham group, Schwann cell-derived exosome treatment group and PBS control group (n=10 per group). The clamp injury was conducted on Schwann cell-derived exosome treatment group and PBS control group. After injury for 24 hours, the mice in the Schwann cell-derived exosome treatment group were injected with exosomes derived from Schwann cells via the caudal vein, and the mice in the PBS control group were injected with PBS via the caudal vein, three times a week for 4 weeks, 25 μL/mice (0.1 g/L) each time. Mice were sacrificed 24 hours after the last injection. After removing the spine, tissue one centimeter above and below the injury site of the spinal cord was isolated for fixation, dehydration, embedding and sectioning. The recruitment of CD31-positive vascular endothelial cells and FSP1-positive fibroblasts in the injured area, as well as the survival of NF200 positive axons was observed by immunofluorescence staining.  RESULTS AND CONCLUSION: Compared with the PBS control group, the number of CD31-positive endothelial cells was decreased (P < 0.01) and the number of FSP1-positive fibroblasts in the injured area was decreased in the mice treated with Schwann cell-derived exosomes (P < 0.05). The number of NF200-positive axons was increased in the Schwann cell-derived exosome treatment group compared with the PBS control group (P < 0.01). These results suggest that Schwann cell-derived exosomes can reduce the recruitment of angiogenesis and scar formation cells in the area after spinal cord injury and promote the recovery of nerve axons.  Figures and Tables | References | Related Articles | Metrics

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Effects of chiral polyethyleneimine/graphene oxide/phenylalanine interface on adhesion and proliferation of multilineage-differentiating stress enduring cells Zhou Jingjing, Sun Yixin, Sheng Yang, Zhang Rong 2023, 27 (10):  1547-1552.  doi: 10.12307/2023.305 Abstract ( 337 )   PDF (3770KB) ( 181 )   Save BACKGROUND: In recent years, multilineage-differentiating stress enduring (Muse) cell has attracted increasing attention due to its pluripotent differentiation capacity and non-tumorigenicity. Cell therapy based on Muse cells has shown exciting results in the animal experiments of many diseases. However, Muse cells face the difficulties of slow proliferation in long-term in vitro culture.   OBJECTIVE: To investigate the effect of chirals interfaces on adhesion and proliferation of Muse cells. METHODS:  The polyethyleneimine/graphene oxide/phenylalanine chiral biointerfaces (PEI/GO/L-Phe and PEI/GO/D-Phe) were constructed based on the layer-by-layer self-assembly method using polyethyleneimine (PEI) as the substrate layer and graphene oxide (GO) and L/D-phenylalanine (L/D-Phe) sequentially deposited. The effect of self-assembled chiral biointerfaces on the adhesion and proliferation behavior of Muse cells was investigated.   RESULTS AND CONCLUSION: (1) PEI/GO/L-Phe and PEI/GO/D-Phe chiral interfaces were successfully constructed based on facile self-assembly technology. (2) The statistical results showed that the chirality on the interface influenced Muse cell behaviors significantly. The initial adhesion and subsequent proliferation of Muse cells were enhanced by the PEI/GO/L-Phe interface, probably owing to the preferred adsorption of proteins, which further promote Muse cell proliferation. Figures and Tables | References | Related Articles | Metrics

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Progress in studies on biological properties of stem cells modified by mRNA m6A methylation Han Weiyu, Zhao Yongchao, Zhao Ranzun 2023, 27 (10):  1584-1592.  doi: 10.12307/2023.313 Abstract ( 342 )   PDF (1826KB) ( 123 )   Save BACKGROUND: Stem cells have the potential of self-renewal and pluripotent directional differentiation, which are necessary for the body to maintain physiological functions, and play an important role in the occurrence and development of various diseases, disease treatment and organ transplantation. Recent studies have found that m6A methylation modification can regulate the biological characteristics of stem cells and play an important role in various diseases.   OBJECTIVE: To mainly summarize the latest research progress of biological process of m6A methylation modification of stem cells, including self-renewal, directional differentiation, and immunological characteristics. METHODS:  Related articles published from 1955 to 2022 were retrieve from PubMed, Web of Science and CNKI databases. The keywords were “stem cell, m6A, RNA methylation, biological characteristics, self-renewal, proliferation, differentiation, immunization” in English and Chinese. Ultimately, we included 88 articles for review.   RESULTS AND CONCLUSION: m6A, as the epigenetic modification with the highest abundance in eukaryotic mRNA, is also the focus of current epigenetic research. It is composed of methyltransferase, demethylase and methyl-binding domain protein, and has become an important transcriptome marker. The conclusions of m6A methylation regulate the biological characteristics as following: (1) m6A methylation modification can be adjusted by related enzymes target transformation, proliferation, cell cycle-related molecular transcription after translation, the expression of key enzymes in the process of DNA replication, to a particular cell differentiation, immune checkpoint molecular expression and their sensitivity to radiation and chemotherapy drugs, and in the treatment of malignant disease, delay condition, improve the prognosis of playing a key role. (2) m6A-related enzymes are closely related to the biological characteristics of stem cell proliferation, self-renewal, directed differentiation and immune regulation, and can be used as a target for drug therapy. (3) The study of m6A methylation on human diseases is still in the basic research stage, and the mechanism of m6A modification in some malignant diseases has not been thoroughly explored. With the development of epigenetics, RNA m6A modification is expected to achieve new breakthroughs in the treatment of malignant diseases and clinical transformation. Figures and Tables | References | Related Articles | Metrics

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Protective effect of stem cells on retinal ganglion cell regeneration Zhang Chunli, Liu Jingchen, Zhou Wenjie, Yu Yongzhen, Tang Cuicui, Zou Xiulan, Zou Yuping 2023, 27 (10):  1593-1602.  doi: 10.12307/2023.277 Abstract ( 545 )   PDF (1861KB) ( 241 )   Save BACKGROUND: Damage to retinal ganglion cells is an important cause of irreversible vision loss, and stem cells have shown a great potential in therapeutic research for the treatment of such diseases, but there are fewer comprehensive descriptions of the relationship between stem cells and ocular tissues and the mechanisms of optic nerve protection.   OBJECTIVE: To describe the progress of stem cell research in retinal ganglion cell protection and regeneration from the source of stem cells and their role in the maintaining of retinal ganglion cell function. METHODS:  “Stem cells, retinal precursor cells, retinal progenitor cells, transdifferentiation” and “retinal ganglion cells, retinal degeneration” were used as Chinese keywords to search in the Wanfang database and CNKI database. “Stem cell, retinal precursor cell, retinal progenitor cell, trans differentiation” and “retinal ganglion cell, RGC, retinal degeneration” were used as English keywords to search in the PubMed database. Finally, 102 articles were included for analysis according to the inclusion criteria.   RESULTS AND CONCLUSION: (1) Retinal stem cells and retinal progenitor cells are present in the mammalian eye, but their scarcity and restricted differentiation potential result in a low regenerative capacity of retinal ganglion cells in the eye. (2) In vitro cultures have shown that many cells in intraocular tissues can differentiate directly into retinal ganglion cells and some have the potential to reprogram into retinal stem cells. Finding conditions that promote the proliferation, differentiation, and reprogramming of these cells could greatly facilitate the intraocular regeneration of retinal ganglion cells. (3) Due to the limitations of current technology, the regeneration of retinal ganglion cells from extraocular stem cells requires multiple processes such as ex vivo culture, induction of differentiation, and surgical reimplantation into the eye. Although the steps are tedious, extraocular stem cells are still the focus of research on retinal ganglion cell regeneration due to their wide source and a large number of cells. (4) Stem cells increase the survival rate of damaged retinal ganglion cells and maintain cell function. Mechanisms such as expression of neurotrophic factors, reduction of the inflammatory response, improvement of ischemia, and promotion of reprogramming of other cells into retinal stem cells are the basis for the optic neuroprotective role of stem cells. (5) In stem cell-based research on retinal ganglion cell regeneration, there are shortcomings such as the risk of tumor formation, the lack of attachment of transplanted cells and the difficulty of integrating them into the host retina, immune rejection, death of transplanted cells, and ethics-related issues that need to be addressed to find an appropriate solution. Figures and Tables | References | Related Articles | Metrics

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Mesenchymal stem cells-derived exosomes in treatment of secondary lymphedema Wang Xinxin, Wang Jingxin 2023, 27 (10):  1603-1609.  doi: 10.12307/2023.344 Abstract ( 411 )   PDF (2456KB) ( 58 )   Save BACKGROUND: A variety kinds of cells can secrete microvesicles because of their paracrine effect, and the smallest microvesicles are called exosomes. Initially, exosomes were recognized as the “metabolic waste” of normal cells. However, they can engage in the regulation of several signaling pathways by transporting special substances such as proteins, lipids, miRNA and ligands or just act as ligands. As one of the most promising therapies, mesenchymal stem cells-derived exosomes are widely used in the study of various diseases and have a significant role in secondary lymphedema.  OBJECTIVE: To review the development and effect of mesenchymal stem cells derived exosomes on secondary lymphedma systematically, and summarize the deficiency of researches.  METHODS:  With the key words and “snowballing ways”, articles about rehabilitation of mesenchymal stem cells-derived exosomes on secondary lymphedma were searched in PubMed, Google Scholar, Embase, Scopus, Wiley, CNKI and Wanfang databases from 2005 to 2022. A total of 58 articles were included finally.  RESULTS AND CONCLUSION: (1) Due to the low immunogenicity of mesenchymal stem cells-derived exosomes, they are widely used in tissue regeneration, visceral fibrosis and many other kinds of diseases. There are rich sources of them, the application of adipose, bone marrow, umbilical cord blood-derived exosomes are most frequent. (2) Mesenchymal stem cells-derived exosomes benefit secondary lymphedema in animal experiments. They can reduce the volume of edema by promoting lymphatic endothelial cell differentiation and reconstructing new lymphatic values. (3) Meanwhile, the exosomes can interact with macrophages and transforming growth factor β and other important factors to regulate the local inflammation as well as the process of fibrosis and fat deposition. However, the specific intervention machanisms are still incomplete. (4) Current researches focus on the animal experiments not touch upon clinical experiments. Besides, there are no clear conclusions about the optimal concentration, proper time and frequency of intervention, so more details and clinical researches are still worthy to be supplied in the future.  Figures and Tables | References | Related Articles | Metrics

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Application and effect of extracellular vesicles in cardiac repair after myocardial infarction Yue Feifei, Song Yu, Wang Xiaobei, Wang Lin 2023, 27 (10):  1610-1617.  doi: 10.12307/2022.978 Abstract ( 356 )   PDF (1676KB) ( 108 )   Save BACKGROUND: As the research progresses, the increasing evidence has shown that mesenchymal stem cells mainly exert their therapeutic effects through paracrine mechanisms, and extracellular vesicles are an important paracrine component of cells. Therefore, extracellular vesicles have attracted considerable interest, especially in the cardiovascular field. OBJECTIVE: To review the progress in the treatment of myocardial infarction with extracellular vesicles and explore the clinical application prospects of extracellular vesicles. METHODS: The relevant articles were searched from CNKI and PubMed databases by computer. The search terms were “extracellular vesicles, myocardial infarction, cardiac repair” in Chinese and “extracellular vesicles, mesenchymal stem cell, embryonic stem cell, induced pluripotent stem cell, cardiomyocyte, target, myocardial infarction, cardiac repair” in English. The time was limited from 2016 to 2021. Finally, 70 articles were included for this review. RESULTS AND CONCLUSION: (1) At present, many studies have successfully used extracellular vesicles to treat myocardial infarction and obtained considerable efficacy. Stem cells, such as mesenchymal stem cells, and some differentiated cell-derived extracellular vesicles can help the infarcted heart maintain normal physiological structure and function by inhibiting apoptosis of hypoxic cardiomyocytes, promoting angiogenesis in the infarct border zone, inhibiting the inflammation or reducing the fibrosis. (2) The mechanism of some cargoes carried by extracellular vesicles for the repair of myocardial infarction has been clarified, of which many microribonucleic acids play important roles in some pivotal cardiac repair signaling pathways, such as miR-21, miR-486-5p, and miR-144. Therefore, more studies are no longer limited to the application of naturally derived extracellular vesicles, but further load therapeutic drugs in extracellular vesicles or modify the membrane components of extracellular vesicles, thereby improving their myocardium targeting ability and cardiac repair potential. Figures and Tables | References | Related Articles | Metrics

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Opportunities and challenges of COVID-19 therapy using mesenchymal stem cells and their exosomes Zhang Yuqing, Wu Jun 2023, 27 (10):  1618-1625.  doi: 10.12307/2023.267 Abstract ( 333 )   PDF (1817KB) ( 128 )   Save BACKGROUND: Corona Virus Disease 2019 (COVID-19) is a highly contagious, rapidly variable, and dangerous infectious disease. However, no specific and effective treatment for COVID-19 is available until now. The safety and efficacy of mesenchymal stem cells and their exosomes have been well verified in numerous clinical trials. Their immunomodulatory and tissue regeneration capabilities may support them as a prospective therapy for COVID-19 application in the clinic.   OBJECTIVE: To focus on the development, pathogenesis and the current treatment status of COVID-19, efficacy and possible immunomodulatory mechanisms of mesenchymal stem cells and their exosomes for COVID-19 so as to provide new insights into the clinical treatment for the disease in the future. METHODS:  Articles were searched on PubMed and CNKI with the key words of “SARS-CoV-2, COVID-19, cytokine storm, acute respiratory distress syndrome, mesenchymal stem cells, exosomes, immune regulation, tissue repair” in Chinese and English. Finally, 64 articles were collected for this review.   RESULTS AND CONCLUSION: Acute respiratory distress syndrome and acute lung injury caused by cytokine storm are the primary precipitating factors of death in individuals with COVID-19. Mesenchymal stem cells and their exosomes can effectively treat the symptoms of acute respiratory distress syndrome and repair the damaged lung tissue in COVID-19 patients by reducing the cytokine storm and promoting the regeneration of alveolar epithelial cells through the interaction with immune cells and their paracrine effects. All of these investigations confirmed that mesenchymal stem cells and their exosomes can fight the COVID-19 infection, and this might be a promising, safe and effective strategy. However, more preclinical studies and randomized, controlled clinical trials are needed to conduct the biodistribution, metabolic fate, and the potential treatment risks of mesenchymal stem cells and their derived exosomes in vivo to fully exploit their clinical efficacy. Figures and Tables | References | Related Articles | Metrics

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Regulation of Sema3A on oral mesenchymal stem cell function Xing Guoyi, Sun Legang, Ma Xiangrui, Wang Wenlong 2023, 27 (10):  1626-1633.  doi: 10.12307/2023.304 Abstract ( 298 )   PDF (1582KB) ( 67 )   Save BACKGROUND: Studies have found that Sema3A can not only participate in tumor growth, angiogenesis, bone remodeling, immune regulation, and other biological and pathological processes, but also effectively promote the proliferation and differentiation of oral tissue-derived mesenchymal stem cells. Therefore, Sema3A may provide new ideas and potential new targets for the treatment of soft and hard tissue damage caused by oral diseases.   OBJECTIVE: To summarize the various biological functions of Sema3A, focusing on the role of Sema3A in regulating the proliferation, differentiation, and inflammatory environment of oral tissue-derived mesenchymal stem cells and the research progress of related signaling pathways so as to provide a feasible solution for Sema3A to treat oral diseases and repair oral soft and hard tissue defects. METHODS:  Articles related to Sema3A and oral mesenchymal stem cells included in CNKI and PubMed databases from January 1993 to March 2022 were searched. A total of 70 articles were included for review.   RESULTS AND CONCLUSION: (1) Sema3A has a great potential in the field of tissue engineering and is a potential therapeutic factor for various diseases. (2) At present, there are relatively few studies on Sema3A on oral tissue-derived mesenchymal stem cells, but it is basically confirmed that Sema3A can play an active role in the regulation of oral tissue-derived mesenchymal stem cells. (3) The inflammatory environment has a significant inhibitory effect on the proliferation and differentiation of stem cells, but studies have found that Sema3A can effectively regulate the proliferation and differentiation of a variety of oral mesenchymal stem cells in an inflammatory environment, thus playing an important role in inflammatory diseases. (4) Because Sema3A itself has the biological function of bone protection and Sema3A can effectively enhance the stem cell characteristics of oral tissue-derived mesenchymal stem cells and induce their proliferation and differentiation, it has unique advantages on regulating the differentiation of oral tissue-derived mesenchymal stem cells into bone to treat bone defect. (5) Studying that Sema3A regulates the proliferation and differentiation of oral tissue-derived mesenchymal stem cells can become a new idea for the treatment of oral diseases, and make breakthroughs in the field of soft and hard tissue repair and regeneration in the oral cavity. Figures and Tables | References | Related Articles | Metrics

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Neuroprotective effect of stem cell transplantation on cerebral ischemia-reperfusion injury in rats: a systematic review Li Ruixin, Su Gang, Liu Jifei, Xu Dan, Gao Xin, Ma Tianfei, Zhang Zhenchang 2023, 27 (10):  1634-1640.  doi: 10.12307/2023.306 Abstract ( 319 )   PDF (2040KB) ( 95 )   Save OBJECTIVE: To evaluate the effect of stem cell transplantation on the recovery of neurological function in rats with cerebral ischemia-reperfusion injury, in order to provide reference data for clinical application.   METHODS: CNKI, Wanfang, VIP, CBM, PubMed, The Cochrane Library, Web of Science and Embase databases were retrieved before October 19, 2021. A series of randomized controlled trials on stem cell transplantation for cerebral ischemia-reperfusion injury rats were included. Two researchers independently screened the literature and extracted the data. The bias risk was evaluated by SYRCLE animal experiment bias risk assessment tool and the data were analyzed by Stata 16.0 statistical software. RESULTS:  A total of 30 articles meeting inclusion criteria were included. Random effect model analysis results showed that compared with the control group, stem cell transplantation could effectively improve the neurological deficit score [SMD=-1.70, 95%CI(-2.18,-1.21)], reduce the cerebral infarction volume score [SMD=-6.49, 95%CI(-8.87, -4.19)], and inhibit the expression level of tumor necrosis factor α [SMD=-3.23, 95%CI(-4.49, -1.96)].   CONCLUSION: The evidence from the existing animal experiments shows that stem cell transplantation can effectively promote the recovery of nerve function and has a protective effect on the brain of cerebral ischemia-reperfusion injury rats. The results of indirect subgroup comparison showed that the efficacy of bone marrow mesenchymal stem cells was better than other types, and the efficacy of arterial transplantation was better than other approaches. However, the results of this systematic review are limited by the quality and quantity of included studies, and its conclusions and clinical application effects need to be further confirmed by more and higher-quality studies. Figures and Tables | References | Related Articles | Metrics