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08 July 2023, Volume 27 Issue 19 Previous Issue    Next Issue

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Effects of bone marrow mesenchymal stem cells on the structure and function of thymus and spleen in aging rhesus monkeys Pan Hang, Zhu Xiangqing, He jie, Yang Zailing, Tian Chuan, Lyu Guanke, Ruan Guangping, Ye Li, He Zhixu, Shu Liping, Pan Xinghua 2023, 27 (19):  2953-2959.  doi: 10.12307/2023.643 Abstract ( 300 )   PDF (15064KB) ( 43 )   Save BACKGROUND: With the increase of age, the structure and function of the spleen changed, and the thymus gradually atrophied and degenerated after puberty, resulting in immune dysfunction.   OBJECTIVE: To investigate the effect of bone marrow mesenchymal stem cells on the structure and function of thymus and spleen in aging rhesus monkeys. METHODS: Six aging rhesus monkeys with an average age of 25 years were randomly divided into elderly group (n=3) and elderly treatment group (n=3). Rhesus monkeys in the elderly treatment group were infused with the 4th generation bone marrow mesenchymal stem cells (1×107/kg) labeled with superparamagnetic iron nanoparticles through femoral vein once a day for 3 consecutive days. Rhesus monkeys in the elderly group were infused with the same volume of normal saline at the same time. The rhesus monkeys were euthanized 5 months after the last infusion of bone marrow mesenchymal stem cells. The thymus and spleen tissues were obtained. The structural changes of thymus and spleen tissues were observed by hematoxylin and eosin staining. Immunofluorescence staining was used to analyze the expression of T cell subsets and age-related gene protein P21 in thymus tissues. Immunohistochemical staining was used to analyze the expression of T cell subsets and age-related gene protein P21 in spleen tissues. Before euthanized, 5 mL of femoral venous blood was extracted by heparin tube. The levels of tumor necrosis factor-α and interleukin-1α in peripheral blood serum were analyzed by enzyme-linked immunosorbent assay.   RESULTS AND CONCLUSION: (1) Superparamagnetic iron nanoparticles labeled bone marrow mesenchymal stem cells could colonize and play a role in aging thymus and spleen tissues in rhesus monkeys. (2) After transplantation of bone marrow mesenchymal stem cells, the cortex and medulla junction appeared in some tissues of the aged rhesus monkeys, and the adipocytes decreased, and the thymic body appeared, and the structure of thymus changed to normal. The splenic tissue of aged rhesus monkeys showed a clear boundary between red pulp and white pulp, and the edge of the splenic body was more complete, and the macrophages were reduced, and the structure of spleen tissue changed to normal. (3) Compared with the elderly group, the expression of CD3+, CD4+ and CD8+ T cells in senile thymus and spleen tissues in the elderly treatment group showed a trend of increase. The expression of P21 protein in senile thymus and spleen tissues in the elderly treatment group showed a significant downward trend. (4) Compared with the elderly group, the levels of tumor necrosis factor-α and interleukin-1α in peripheral blood of the elderly treatment group showed a significant downward trend. (5) These results indicated that transplantation of bone marrow mesenchymal stem cells could improve the structure and function of thymus and spleen tissues in aged rhesus monkeys. Figures and Tables | References | Related Articles | Metrics

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Effects of iRoot BP Plus combined with Yunnan Baiyao on mineralization of dental pulp stem cells under inflammatory conditions Zhao Ying, Liang Guangzhi, Zhou Yuqi, Wang Tianqi, Liu Yunxia, Liu Xiaoying, Zhang Juanjuan, Sun Yan 2023, 27 (19):  2960-2967.  doi: 10.12307/2023.606 Abstract ( 250 )   PDF (3120KB) ( 81 )   Save BACKGROUND: As a permanent preservation of living pulp, pulpotomy has been gradually applied in clinical treatment. The selection and application of pulpotomy materials can greatly enhance its clinical efficacy and expand its application range.   OBJECTIVE: To study the effects of Yunnan Baiyao, iRoot BP Plus and their combination on the mineralization of pulp stem cells under the condition of inflammation. METHODS: Human primary dental pulp stem cells were cultured by tissue block method, and the effects of Yunnan Baiyao and iRoot BP Plus on the proliferation of dental pulp stem cells were determined by MTT assay to determine the optimal concentration of intervention quality. Passages 3-6 dental pulp stem cells were divided into five groups: normal control group, inflammatory control group, Yunnan Baiyao group, iRoot BP Plus group, and Yunnan Baiyao + iRoot BP Plus group. Cells in the inflammatory control group, Yunnan Baiyao group, iRoot BP Plus group, and Yunnan Baiyao + iRoot BP Plus group were treated with 1 μg/mL lipopolysaccharide for 2 hours to establish models and then stimulated with 75 μg/mL Yunnan Baiyao, 100 μg/mL iRoot BP Plus alone and their combination. Effects of drugs on cellular mineralization were determined by alkaline phosphatase assay, alizarin red S staining, real-time-PCR and western blot assay.   RESULTS AND CONCLUSION: (1) Compared with the inflammatory control group, Yunnan Baiyao, iRoot BP Plus and their combination inhibited the mRNA expression of tumor necrosis factor-α (P < 0.001). The mRNA expression of tumor necrosis factor-α in Yunnan Baiyao + iRoot BP Plus group was significantly lower than that in Yunnan Baiyao group and iRoot BP Plus group (P < 0.001). (2) Compared with the inflammatory control group, the number of mineralized nodules and alkaline phosphatase activity were significantly increased after Yunnan Baiyao, iRoot BP Plus, and their combined application. The number of mineralized nodules and alkaline phosphatase activity in Yunnan Baiyao + iRoot BP Plus group were higher than those in Yunnan Baiyao and iRoot BP Plus groups (P < 0.001). (3) Compared with the inflammatory control group, the mRNA expression levels of DSPP, IBSP and MEPE increased after Yunnan Baiyao, iRoot BP Plus, and their combined application (P < 0.001). The mRNA expression levels of DSPP, IBSP, and MEPE in Yunnan Baiyao + iRoot BP Plus group were higher than those in Yunnan Baiyao group and iRoot BP Plus group (P < 0.001). (4) Compared with the inflammatory control group, phosphorylation of Akt and mTOR was increased in Yunnan Baiyao group and Yunnan Baiyao + iRoot BP Plus group (P < 0.001). (5) The results show that both Yunnan Baiyao and iRoot BP Plus can promote the mineralization of dental pulp stem cells, and the combined application of Yunnan Baiyao and iRoot BP Plus has a more significant mineralization effect. The effect of Yunnan Baiyao on promoting the mineralization of dental pulp stem cells is associated with the Akt/mTOR pathway. Figures and Tables | References | Related Articles | Metrics

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Effect of glycogen synthase kinase-3 beta inhibitor Tideglusib on proliferation and osteogenic differentiation of rat bone marrow mesenchymal stem cells under high glucose microenvironment Luo Wenhao, Feng Le, Huang Haixia, Liu Min, Wang Pin 2023, 27 (19):  2968-2974.  doi: 10.12307/2023.620 Abstract ( 190 )   PDF (2647KB) ( 46 )   Save BACKGROUND: High glucose condition can inhibit the proliferation and osteogenic differentiation of bone marrow mesenchymal stem cells, and how to improve the biological activity of osteoblasts in high glucose conditions is the key to improve osseointegration in diabetic patients.   OBJECTIVE: To investigate the effect of Tideglusib, a non-ATP-competitive specific glycogen synthase kinase-3β (GSK-3β) inhibitor, on the osteogenic differentiation of rat bone marrow mesenchymal stem cells under high glucose conditions. METHODS: Rat bone marrow mesenchymal stem cells were cultured and purified by whole bone marrow apposition method. Bone marrow mesenchymal stem cells were divided into four groups as follows: normal control group (5.5 mmol/L glucose), Tideglusib group (5.5 mmol/L glucose + 20 nmol/L Tideglusib), high glucose group (25.5 mmol/L glucose), and Tideglusib + high glucose group (25.5 mmol/L glucose+20 nmol/L Tideglusib). (1) The proliferation activities of cells were detected by CCK-8 assay. (2) Alkaline phosphatase activity was detected at 4 and 7 days after osteogenic differentiation in each group. (3) Calcium nodules were detected by alizarin red staining at 21 days after osteogenic differentiation in each group. (4) Phalloidin staining was used to observe the adhesion morphology of each group after 24 hours of inoculation. (5) RT-qPCR was used to detect the mRNA expression of osteogenic genes Runx2 and OPN. Western blot assay was used to detect the protein expression of β-catenin and p-GSK-3β.   RESULTS AND CONCLUSION: (1) Tideglusib (20 nmol/L) not only significantly promoted the proliferation of bone marrow mesenchymal stem cells (P < 0.05), but also reversed the inhibitory effect of the high glucose on the proliferation of bone marrow mesenchymal stem cells (P < 0.05). (2) Tideglusib (20 nmol/L) significantly reduced the inhibitory effect of high glucose conditions on alkaline phosphatase activity (P < 0.05) and promoted the formation of calcified nodules under high glucose conditions (P < 0.05). (3) Tideglusib (20 nmol/L) could improve the adhesion morphology of bone marrow mesenchymal stem cells damaged by high glucose conditions. (4) Compared with the high glucose group, Tideglusib (20 nmol/L) up-regulated the mRNA expression of osteogenic genes Runx2 and OPN under the high glucose conditions (P < 0.05). (5) Compared with the high glucose group, Tideglusib (20 nmol/L) upregulated the expression of Wnt/β-catenin pathway related target β-catenin protein and down-regulated the expression of p-GSK-3β protein under high glucose conditions (P < 0.05). (6) The results showed that Tideglusib (20 nmol/L) could reverse the damage of high glucose conditions on the initial adhesion morphology, cell proliferation and osteogenic differentiation of bone marrow mesenchymal stem cells by activating Wnt/β-catenin signaling pathway. Figures and Tables | References | Related Articles | Metrics

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Safety of bendamustine, etoposide, cytarabine, melphalan (BeEAM) as preconditioning in autologous hematopoietic stem cell transplantation for patients with lymphomas Kong Dai, Wang Xinkai, Pei Xiaohang, Lian Cheng, Niu Xiaona, Bai Yanliang, Niu Junwei, Zhu Zunmin, Liu Zhongwen 2023, 27 (19):  2975-2979.  doi: 10.12307/2023.623 Abstract ( 781 )   PDF (1494KB) ( 92 )   Save BACKGROUND: In recent years, the application of new drugs such as monoclonal antibodies, small molecule targeted drugs and immunotherapy has significantly improved the short-term efficacy and long-term survival of patients with malignant lymphoma, but autologous hematopoietic stem cell transplantation still plays an important role in the overall treatment of malignant lymphoma. Preconditioning is a very important step in the whole process of autologous hematopoietic stem cell transplantation, but there is no standard preconditioning program at present.   OBJECTIVE: To investigate the safety and effectiveness of Bendamustine, Etoposide, Cytarabine (Melphalan) BeEAM as preconditioning in autologous hematopoietic cell transplantation for patients with lymphomas.  METHODS: From July 5, 2021 to May 31, 2022, 11 patients with lymphoma who underwent autologous hematopoietic stem cell transplantation with BeEAM preconditioning regimen in Department of Hematology of Henan Provincial People’s Hospital were enrolled in the study. The clinical characteristics, pretreating-related non-hematologic toxicity, and hematopoietic reconstitution of the patients were analyzed. RESULTS AND CONCLUSION: (1) The non-hematological toxicity of BeEAM pretreatment regimen mainly included oral mucositis, diarrhea and fever at granulosa stage, with the incidence of 72.7%, 63.6%, 90.9%, respectively. (2) The median time of neutrophil implantation was 9(8-11) days, and that of platelet implantation was 10(7-16) days. (3) BeEAM pretreatment regimen for autologous hematopoietic stem cell transplantation of lymphoma has controllable non-hematologic toxicity and rapid hematopoietic reconstruction, with transplant-related mortality of 0% at 100 days and transplant-related mortality of 0% at the end of follow-up period, showing good efficacy and safety. Chinese Clinical Trial Registry: identifier No. ChiCTR2100048295. Figures and Tables | References | Related Articles | Metrics

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Effect of the frequency of bone marrow mesenchymal stem cell infusion on pulmonary fibrosis in silicosis rats Zhang Ying, Huang Ming, Lu Fengrong, Cai Tingfeng, Li Ruiwen 2023, 27 (19):  2980-2985.  doi: 10.12307/2023.634 Abstract ( 285 )   PDF (3052KB) ( 49 )   Save BACKGROUND: Preliminary studies of the research team have shown that bone marrow mesenchymal stem cells can reduce pulmonary inflammation and pulmonary fibrosis in rats caused by silica dust, and no obvious rejection or side effects were found. However so far, almost all reports on the treatment of silicosis animals with bone marrow mesenchymal stem cells are single infusion, and there is no report comparing the effect of multiple repeated infusions and single infusions.   OBJECTIVE: To investigate the effect of frequency of bone marrow mesenchymal stem cell infusion on pulmonary fibrosis in rats exposed to silica dust.  METHODS: SD rats were randomly divided into normal control group, model group, single infusion group, and multiple infusion group, with 6 rats in each group. Rats in the latter three groups were treated with 1 mL SiO2 suspension at a concentration of 30 mg/mL by tracheal injection, and rats in normal control group were treated with equal volume of normal saline. The single infusion group was injected with 5×109 L-1 0.5 mL bone marrow mesenchymal stem cell suspension via caudal vein on day 28 after dust exposure; the multiple infusion group was injected with bone marrow mesenchymal stem cell suspension on day 28, 35 and 42 after dust exposure; the model group and the normal control group were injected with equal volume of normal saline. After 84 days of experiment, lung CT scan was performed to weigh and calculate lung coefficient in each group. Hematoxylin-eosin staining and Masson staining were performed to detect the levels of hydroxyproline in lung tissue and transforming growth factor β1 in serum.   RESULTS AND CONCLUSION: (1) Lung CT images showed that no abnormality was detected in rat lungs of the normal control group. In model group, small granular high-density shadows with diffused distribution and different sizes were observed in both lungs, as well as reticular fiber shadow or cable shadow. The density of the granular shadow distribution and the fiberoptic area were all decreased in the rat lung field of the single-infusion and multiple-infusion groups. (2) Hematoxylin-eosin staining showed that diffuse silicon nodules were seen in the model group, which were fused into films in a large area and infiltrated by lymphocytes. In the single infusion group, there were silicon nodules, local fusion, fibrous tissue hyperplasia, and lymphocyte infiltration in alveolar septum. In the multiple infusion group, a small number of silicon nodules, interstitial fibrous hyperplasia and lymphocyte infiltration were observed. (3) Masson staining showed that in the model group, massive collagen proliferation was seen; small collagen fiber was found in the widened alveolar interval and bronchus and vessels the in multiple infusion group; collagen fibers in single infusion group were between model group and multiple infusion group. (4) Hydroxyproline content in lung tissue, lung collagen volume fraction and serum transforming growth factor β1 level from low to high were normal control, multiple infusion, single infusion, and model groups. Lung hydroxyproline content and collagen volume fraction varied significantly between the groups (P < 0.05). There was significant difference in transforming growth factor β1 level between all the other groups (P < 0.05) except for the model group and the single infusion group as well as single and multiple infusion groups (P > 0.05). (5) Results indicate that multiple infusion of bone marrow mesenchymal stem cells is more effective than single infusion on pulmonary fibrosis induced by silica dust. Figures and Tables | References | Related Articles | Metrics

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Umbilical cord mesenchymal stem cell-derived exosomes treated with hypoxic preconditioning inhibits proliferation of pulmonary artery smooth muscle cells Zhang Yuwei, Liu Chuanchuan, Mao Jiaqi, Zhang Qingqing, Liu Hong, Chen Ying, Ma Lan 2023, 27 (19):  2986-2992.  doi: 10.12307/2023.624 Abstract ( 297 )   PDF (3395KB) ( 83 )   Save BACKGROUND: Studies have shown that exosomes can improve hypoxic pulmonary hypertension. There are significant differences in the function of exosomes from different sources and different environments. The effect of hypoxic preconditioning with umbilical cord mesenchymal stem cell-derived exosomes on the proliferation of rat pulmonary artery smooth muscle cells is unclear.   OBJECTIVE: To explore the effects of umbilical cord mesenchymal stem cell-derived exosomes pretreated with hypoxia on the hypoxia-induced proliferation of rat pulmonary artery smooth muscle cells. METHODS: Primary human umbilical cord mesenchymal stem cells were isolated and cultured by tissue adhesion method, and the exosomes of human umbilical cord mesenchymal stem cells were extracted by ultrafiltration. Rat pulmonary artery smooth muscle cells were isolated by tissue digestion. The inhibition rate of cell proliferation after the intervention of exosomes with different concentrations was measured by cell counting kit-8 assay to determine the appropriate mass concentration and intervention time for the action of exosomes. Passage 3 pulmonary artery smooth muscle cells were divided into normoxic control group, hypoxic control group, hypoxic+normoxic exosome group and hypoxic+hypoxic exosome group. 5-Ethynyl-2'-deoxyuridine method was used to detect the proliferation of cells in each group. The expression level of nuclear proliferation antigen protein was detected by western blot assay.   RESULTS AND CONCLUSION: (1) Compared with the normoxic control group, the proliferation of pulmonary artery smooth muscle cells in the hypoxic control group was significantly increased. Compared with the hypoxic control group, the cell proliferation ability of the hypoxic+normoxic exosome group decreased, and the proliferation ability of the hypoxic+hypoxic exosome group decreased more significantly. (2) Compared with the normoxic control group, the expression level of nuclear proliferation antigen protein was increased in the hypoxic control group. Compared with the hypoxic control group, the expression level of nuclear proliferation antigen protein was slightly reduced in the hypoxic+normoxic exosome group. The expression level of nuclear proliferation antigen protein was significantly diminished in the hypoxic+hypoxic exosome group. (3) The results showed that the exosomes derived from human umbilical cord mesenchymal stem cells pretreated with hypoxia had the ability to inhibit the proliferation of pulmonary artery smooth muscle cells. Figures and Tables | References | Related Articles | Metrics

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miR-29a inhibits hydrogen peroxide-induced astrocyte apoptosis by regulating aquaporin-4 Zhu Lin, Guo Shiwu, Liu Jinbo, Zou Hongjun 2023, 27 (19):  2993-2998.  doi: 10.12307/2023.670 Abstract ( 219 )   PDF (2788KB) ( 51 )   Save BACKGROUND: The role of miR-29a and aquaporin-4 in astrocyte injury has been demonstrated. However, the underlying mechanisms remain largely unknown.   OBJECTIVE: To investigate the effects of the regulation of aquaporin-4 by miR-29a on hydrogen peroxide-induced astrocyte injury. METHODS: (1) Primary cultured mouse astrocytes were used to study the damage response of mouse astrocytes induced by different concentrations of hydrogen peroxide, and the cells were divided into control, hydrogen peroxide, hydrogen peroxide + empty vector, and hydrogen peroxide + miR-29a overexpression groups. The survival rate of mouse astrocytes was detected by MTT assay. The protein expression of apoptosis-related proteins (Bcl-2, Bax, and cleaved-Caspase-3), aquaporin-4 and glial fibrillary acidic protein was detected by western blotting. The expression of miR-29a in mouse astrocytes was detected by quantitative reverse transcription-polymerase chain reaction. Mouse astrocyte apoptosis was detected by flow cytometry. (2) Twelve female BALB/c  mice were randomly divided into empty vector and miR-29a overexpression groups with six mice in each group. A T10 spinal cord contusion injury mouse model was established, and the injection of recombinant lentiviral vectors (empty and miR-29a overexpression vectors) was administered after modeling. The expression of aquaporin-4 and glial fibrillary acidic protein at the spinal cord injury site in mice was detected by immunohistochemical staining at 7 days after surgery.   RESULTS AND CONCLUSION: (1) The activity of astrocytes and the expression of anti-apoptosis protein Bcl-2 were decreased, while the expression of pro-apoptosis proteins Bax and cleaved-caspase-3 was increased in a concentration-dependent manner after hydrogen peroxide-induced injury. In mouse astrocytes with hydrogen peroxide-induced injury, miR-29a expression was decreased, while protein expression of aquaporin-4 and glial fibrillary acidic protein was significantly increased; overexpression of miR-29a inhibited protein expression of aquaporin-4 and apoptosis. Aquaporin-4 may be a downstream target gene of miR-29a as predicted using informatics software. (2) Overexpression of miR-29a at the injury site inhibited the protein expression of aquaporin 4 and glial fibrillary acidic protein in the spinal cord contusion injury mouse model compared with that of the empty vector injection group. (3) These findings suggest that the regulation of aquaporin 4 by miR-29a can inhibit hydrogen peroxide-induced astrocyte apoptosis. Figures and Tables | References | Related Articles | Metrics

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Effects of lentivirus mediated silencing of Smad2 gene on osteogenic differentiation of human dental pulp stem cells Wang Chang, Sun Shuai, Chen Xiaotao, Zhang Xiaoli 2023, 27 (19):  2999-3004.  doi: 10.12307/2023.660 Abstract ( 256 )   PDF (2067KB) ( 129 )   Save BACKGROUND: The specific regulatory mechanism underlying osteogenic differentiation of human dental pulp stem cells is still unclear. Therefore, studying the specific mechanism is of great significance for the application of stem cells in tissue engineering.   OBJECTIVE: To investigate the role of lentivirus mediated silencing of Smad2 gene in the osteogenic differentiation of human dental pulp stem cells. METHODS: The third generation of human dental pulp stem cells were cultured and divided into blank control group, negative control group, Smad2-shRNA group, and Smad2-shRNA+transforming growth factor-β3 (TGF-β3) group. The mRNA expression of osteogenic related genes Runx2, osteocalcin, Smad2, Smad3, and Smad4 in human dental pulp stem cells was measured by qRT-PCR. The protein expression levels of Runx2, osteocalcin, Smad2/Smad3, p-Smad2/Smad3, and Smad4 in human dental pulp stem cells were measured by western blot assay. Alizarin red staining was performed in each group on the 7th and 14th days of culture.   RESULTS AND CONCLUSION: (1) The mRNA expressions of Runx2, osteocalcin, Smad2, Smad3, and Smad4 in the Smad2-shRNA group were significantly lower than those in the negative control group and blank control group (P < 0.05). The mRNA expressions of osteocalcin, Smad2, Smad3, and Smad4 were significantly increased in the Smad2-shRNA+TGF-β3 group compared with the Smad2-shRNA group (P < 0.05). (2) The protein expressions of Runx2, osteocalcin, and Smad2/Smad3 in the Smad2-shRNA group were significantly lower than those in the negative control group and blank control group (P < 0.05). The protein expressions of RUNX2, osteocalcin, Smad2/Smad3, and Smad4 were significantly increased in the Smad2-shRNA+TGF-β3 group compared with the Smad2-shRNA group (P < 0.05). (3) Culture with conventional medium and transfection with lentiviral vector could not induce the osteogenic differentiation of human dental pulp stem cells, while TGF-β3 could positively regulate the osteogenic differentiation of human dental pulp stem cells. (4) All these findings indicate that theTGF-β/Smad2 signal transduction pathway plays an important role in the osteogenic differentiation of human pulp stem cells. Figures and Tables | References | Related Articles | Metrics

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Different concentrations of calcium ions interfere with the proliferation and osteogenic differentiation of human periodontal ligament stem cells Li Yinghui , Qi Fangfang, Han Xing , Zhao Liru , Ma Wensheng 2023, 27 (19):  3005-3010.  doi: 10.12307/2023.639 Abstract ( 280 )   PDF (8560KB) ( 117 )   Save BACKGROUND: As a second messenger, Ca2+ regulates many physiological processes, but its biological effect on the osteogenic differentiation of periodontal ligament stem cells is still unclear.   OBJECTIVE: To investigate the effect of Ca2+ on the osteogenic differentiation of human periodontal ligament stem cells. METHODS: The proliferation ability and osteogenic differentiation of the third generation human periodontal ligament stem cells were detected by the complete medium containing Ca2+ at the concentrations of 0 (control group), 1, 2, 5, 10, and 15 mmol/L and osteogenic induction solution.  CCK-8 assay was used to detect cell proliferation at 1, 3, 5, and 7 days. Real-time PCR and western blot assay were used to detect the expression levels of genes and proteins related to osteogenic differentiation factors RUNX2, OPN and OCN on days 3 and 7 of osteogenic induction. Alizarin red staining was performed on day 14 to analyze the osteogenic mineralization of human periodontal ligament stem cells.   RESULTS AND CONCLUSION: (1) CCK-8 assay showed that the proliferation ability of human periodontal ligament stem cells in 2 and 5 mmol/L groups was better than that in control group on days 5 and day 7 (P < 0.05).  (2) On day 7 after in vitro osteogenic induction, the expression levels of osteogenic genes RUNX2, OPN and OCN in human periodontal ligament stem cells of 5 and 10 mmol/L groups were higher than those in control group (P < 0.05). (3) After 14 days of in vitro osteogenic induction, the numbers of mineralization nodules of human periodontal ligament stem cells in Ca2+ groups were higher than that in control group (P < 0.05). (4) These results suggest that Ca2+ can promote the proliferation and osteogenic differentiation of human periodontal ligament stem cells in a certain concentration range. Figures and Tables | References | Related Articles | Metrics

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Resveratrol promotes the proliferation and osteogenic differentiation of stem cells from human exfoliated deciduous teeth Yue Haiyun, Sun Yinxue, Bi Yingchun 2023, 27 (19):  3011-3016.  doi: 10.12307/2023.640 Abstract ( 190 )   PDF (1972KB) ( 62 )   Save BACKGROUND: Resveratrol is a natural non-flavonoid polyphenol compound. Studies have shown that resveratrol has antioxidant, anti-inflammatory, anti-aging and anti-tumor activities, and promotes the osteogenic differentiation of bone marrow mesenchymal stem cells. However, whether resveratrol can promote the osteogenic differentiation of stem cells from human exfoliated deciduous teeth is even not expounded.   OBJECTIVE: To investigate the effects of resveratrol on the proliferation and osteogenic differentiation of stem cells from human exfoliated deciduous teeth. METHODS: Human stem cells from human exfoliated deciduous teeth were isolated and cultured by tissue block method. Osteogenic induced stem cells from human exfoliated deciduous teeth were treated with different concentrations of resveratrol. Cell activity was detected by CCK-8 assay. The number of mineralized nodular cells was detected by alizarin red staining. mRNA expression of osteogenic genes was detected by RT-qPCR and protein expression of Runt-related transcription factor 2 was detected by western blot assay.   RESULTS AND CONCLUSION: (1) CCK-8 assay results showed that after 3 days of treatment, resveratrol at concentrations of (20, 40, 80, and 100 μmol/L) significantly inhibited the proliferation of stem cells from human exfoliated deciduous teeth. Therefore, 1, 5, and 10 μmol/L resveratrol could be used to treat stem cells from human exfoliated deciduous teeth in subsequent experiments to detect their effects on osteogenic differentiation. (2) With 10 μmol/L  resveratrol treatment, the number of osteogenic nodules of stem cells from human exfoliated deciduous teeth increased significantly compared with the control group. (3) Alkaline phosphatase, Runt-related transcription factor 2, and osteocalcin mRNA expression levels were increased after 10 μmol/L resveratrol treatment compared with the control group. (4) Runt-related transcription factor 2 protein expression levels of resveratrol treatment groups increased in a concentration-dependent manner compared with the control group. (5) The results indicate that appropriate concentration of resveratrol promotes the proliferation and osteogenic differentiation of stem cells from human exfoliated deciduous teeth.  Figures and Tables | References | Related Articles | Metrics

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Obtaining microglia-like cells after mouse corneal epithelial cell induction Xu Huifang, Shan Ping, Li Lijuan 2023, 27 (19):  3017-3022.  doi: 10.12307/2023.667 Abstract ( 139 )   PDF (2316KB) ( 81 )   Save BACKGROUND: Microglial cells are the predominant immune cells of the central nervous system and are important for the study of the development and treatment of many diseases. However, the methods for obtaining individualized cells in vitro are still lacking.   OBJECTIVE: To establish a new microglia induction culture system to induce mouse corneal epithelial cells into microglia-like cells. METHODS: Corneal epithelial tissues of 2-week-old mice were lysed to obtain epithelial cells, and modified media containing interleukin-34 (100 ng/mL), colony stimulating factor 1 (5 ng/mL), transforming growth factor β (1 ng/mL), interleukin-6 (1 ng/mL), and recombinant vascular endothelial growth factor (1 ng/mL) were successively added. Treatment lasted up to 16 days. Cell properties were evaluated after induction by transcriptional level, protein expression level, subcellular localization, flow cytometry and morphological observation.   RESULTS AND CONCLUSION: After induction, microglia-like cells which express characteristic molecules of TMEM119, CXCL11, CD11b and CD68 were obtained. Morphological observation, flow cytometry and fluorescence analysis confirmed that the expression products of TMEM119, CXCL11, CD11b and CD68 microglia had high abundance, which was very similar to microglia. Figures and Tables | References | Related Articles | Metrics

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miR-889-3p inhibits osteogenic differentiation of adipose-derived mesenchymal stem cells by targeting Runx2 Zhang Yaotian, Cui Jun, Liu Jingyi 2023, 27 (19):  3023-3028.  doi: 10.12307/2023.616 Abstract ( 249 )   PDF (2402KB) ( 37 )   Save BACKGROUND: Studies have shown that miR-889-3p is able to participate in the regulation of the proliferation and differentiation of a variety of cells, but its effect on the osteogenic differentiation of adipose-derived mesenchymal stem cells remains unclear.   OBJECTIVE: To investigate the regulation of miR-889-3p in osteogenic differentiation of adipose-derived mesenchymal stem cells. METHODS: Adipose-derived mesenchymal stem cells from SD rats were isolated and cultured in vitro, transfected with miR-889-3p mimics, Mir-889-3p inhibitor and negative control (miR-NC) then induced osteogenic differentiation. RT-PCR and western blot assay were used to detect alkaline phosphatase activity, Runx2, osteocalcin, osteopontin, Osterix and other osteogenic related mRNA and protein expression levels. Adipose-derived mesenchymal stem cells were co-transfected with wild-type Runx2 and mutant Runx2 with miR-889-3p mimic and miR-NC, respectively. Luciferase reporter gene assay was used to detect the targeting relationship between miR-889-3p and Runx2.   RESULTS AND CONCLUSION: (1) The expression level of miR-889-3p decreased gradually with the prolongation of osteogenic induction. (2) The number, size, and color depth of mineralized nodules in the miR-889-3p inhibitor group were significantly higher than those in the miR-889-3p mimic group and miR-NC group on days 7 and 14 of osteogenic induction (P < 0.05). (3) Overexpression of miR-889-3p significantly suppressed alkaline phosphatase activity, Runx2, osteocalcin, osteopontin, Osterix mRNA and protein expression, whereas the knockdown of miR-889-3p remarkably enhanced osteogenesis-related mRNA and protein expression. (4) The results of dual-luciferase reporter gene assay showed that overexpression of miR-889-3p significantly reduced the luciferase activity of wild-type Runx2. (5) These results suggest that miR-889-3p negatively regulates osteogenic differentiation of adipose-derived mesenchymal stem cells by targeting Runx2. Figures and Tables | References | Related Articles | Metrics

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Effects of pretreated exosomes on cell proliferation, differentiation and apoptosis Chen San, Yang Runze, Wu Jiayuan 2023, 27 (19):  3029-3039.  doi: 10.12307/2023.661 Abstract ( 277 )   PDF (5379KB) ( 125 )   Save BACKGROUND: The biological functions and characteristics of pretreated exosomes have been extensively studied and verified in the treatment of some diseases and achieved good results, suggesting that they may also have broader prospects in the field of tissue regeneration and clinical applications. OBJECTIVE: To mainly explore the pretreatment methods of donor cells of pretreated exosomes and the influence of pretreatment factors on the function of exosomes and to summarize the effects and current status of clinical application of different pretreated exosomes on cell proliferation, differentiation, and apoptosis. METHODS: PubMed, Web of Science, CNKI, and WanFang databases were searched for relevant articles. The retrieval terms were “exosomes, small extracellular vesicles, pretreatment” in Chinese and “pretreatment, cell factor, hypoxia, ischemia” in English. A total of 75 articles were finally included in result analysis.  RESULTS AND CONCLUSION: (1) Although the cell-derived exosomes have good biocompatibility and low immunogenicity, they have some shortcomings, such as low yield and weak targeting. Their biological properties highly depend on the state, type, and culture environment of cells. Pretreatment of cells and their microenvironment can affect the contents and level of the obtained exosomes. (2) Common exosome pretreatment methods include cytokines, anoxia/hypoxia, drugs and physical intervention. The exosomes obtained by different cells or different pretreatment methods may have different biological characteristics. (3) Compared with the untreated exosomes, the pretreated exosomes can regulate cell proliferation and apoptosis, osteogenic differentiation, and angiogenesis. Their functional properties have obvious advantages and play a biological role efficiently. (4) The pretreated exosomes play an important role in tissue repair and disease treatment, which have been successfully used in the treatment of ischemic diseases, immune function regulation, and inflammatory diseases. (5) Pretreatment, as an effective stimulus for cell “modification,” has shown outstanding advantages in the field of exosome research. It can not only be applied to disease treatment and regulation, but also has a good application prospect in tissue engineering regeneration and repair. As an adaptive strategy to improve exosome production and biological effects, its specific mechanism and functional conditions need to be further studied. Figures and Tables | References | Related Articles | Metrics

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Exosomal miRNA in the repair mechanism of degenerative diseases of the spine and joints Zhao Yan, Xia Qiuqiu, Xiang Shaojie, Mao Qiming, Kong Weijun, Du Qian, Liao Wenbo, Xin Zhijun 2023, 27 (19):  3040-3051.  doi: 10.12307/2023.635 Abstract ( 302 )   PDF (3274KB) ( 58 )   Save BACKGROUND: Degenerative spondylolisthesis mainly consists of intervertebral disc degeneration and osteoarthritis. In recent years, the use of exosomal miRNAs to treat degenerative spinal joint disease by promoting autophagy and cell proliferation and migration has become a promising emerging therapeutic option.   OBJECTIVE: To review the research progress of exosomal miRNA in the development, diagnosis and treatment mechanism of intervertebral disc degeneration and osteoarthritis. METHODS: The first author searched the PubMed database using “intervertebral disc degeneration; osteoarthritis; exosomes; miRNA; autophagy; extracellular matrix; apoptosis; cell proliferation; pyroptosis; biomarkers; mechanistic pathways” as the keywords. Finally, 133 English articles were summarized.   RESULTS AND CONCLUSION: (1) The main physiopathological feature of exosomal miRNA for the treatment of degenerative spinal joint diseases is to treat degenerative spinal joint diseases by promoting autophagy and cell migration and proliferation, inhibiting extracellular matrix degradation, apoptosis, cell pyroptosis and inflammatory effects in several ways. The same exosomal miRNA is able to participate in different physiopathological processes of the same disease. (2) The mechanisms and pathways of action of exosomes in the treatment of degenerative spondylolisthesis occur mainly through the Wnt/β-catenin pathway, mTOR, NLRP3, nuclear factor-κB, MAPK and other signaling pathways; the MAKP signaling pathway is a common signaling pathway in exosomal miRNA therapy to improve the process of intervertebral disc degeneration and osteoarthritis disease, which is significant for finding common targets in intervertebral disc degeneration, osteoarthritis disease and other degenerative diseases of the spine and joints. (3) The same miRNA family can be involved in the repair of different degenerative lesions, which has a significant implication for the exploration or synthesis of new type of exosomal miRNA to treat other degenerative diseases of the spine and joints, but further studies are needed to investigate the safety and adverse effects of exosomal miRNA therapy in spinal and joint degenerative diseases. Figures and Tables | References | Related Articles | Metrics

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Recent advances of engineered exosomes and challenges on clinical translational research Zhang Qi, Yu Mei, Liu Lei, Tian Weidong 2023, 27 (19):  3052-3060.  doi: 10.12307/2023.636 Abstract ( 720 )   PDF (2039KB) ( 65 )   Save BACKGROUND: Currently, exosomes were widely attracted as a new form of drug carrier by many researchers. Based on the modification by different bioengineering techniques, natural exosomes were engineered to obtain the enhanced exosomal characteristics and functions.   OBJECTIVE: To review the preparation strategies, research progress and challenges in clinical translation of engineered exosomes. METHODS: We searched the articles on PubMed database and FDA online statements with the key words of “extracellular vesicles, exosomes, drug delivery, engineering, engineered, treatment, clinical translation, scale production, isolation, characterization, quality control, storage, safety” in English. Finally, 73 articles and 1 statement met the criteria for review.   RESULTS AND CONCLUSION: (1) Engineered exosomes can be produced by cell engineering and exosome engineering. The enhanced properties of engineered exosomes manufactured by the two strategies have been verified in basic research, which proves that they have great clinical application prospects. However, both of them have a series of problems such as biosafety and low drug loading efficiency that need to be solved. (2) Engineered exosomes have been proven to have great clinical application potential in various fields such as tumor, cardiovascular disease, tissue regeneration and repair, and nervous system diseases, and have shown better therapeutic effect and targeting ability than natural exosomes. (3) Clinical transformation of engineered exosomes faces many problems and challenges. All kinds of common cells can be used for exosome production and manufacturing. Changes in cell number and culture condition will lead to variation in exosomes. Expanding the scale of cell culture is the most direct method for mass production of exosomes. Different extraction methods will affect the yield and the homogeneity of exosome. The methods on scale culture, isolation and extraction need to be standardized. Characterization and quantification can predict the expected therapeutic potential of drug-loaded exosome systems. It is necessary to further develop gold standards for the quantification of exosomes and the description of molecular and physical characteristics. Exosome products require additional quality control to ensure that the exosome end products meet key quality attributes. Freeze-drying is most conducive process to the commercialize exosome therapeutic drugs. Guideline for the safety and efficacy of exosomes product has not been issued yet, and it is necessary to improve existing methods or find new methods to prove the safety and efficacy of engineered exosomes. (4) Although none of the engineered exosomes has been officially clinically applied yet, their therapeutic potential is indisputable. There is still a long way to go before commercial engineered exosome products are ready for the market.  Figures and Tables | References | Related Articles | Metrics

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Adipose-derived mesenchymal stem cell exosomes for treating traumatic central nervous system injury Liu Chuang, Tan Longwang, Zhou Heshan, Zhang Chi 2023, 27 (19):  3061-3069.  doi: 10.12307/2023.630 Abstract ( 284 )   PDF (2012KB) ( 53 )   Save BACKGROUND: Adipose-derived mesenchymal stem cell exosomes have the characteristics of strong damage repair function, high safety, passing blood-brain barrier, convenient material acquisition, and easy mass production, which makes it has the great potential in the treatment of traumatic central nervous system injuries.   OBJECTIVE: To review the experimental research on the application of adipose-derived mesenchymal stem cell exosomes in the treatment of traumatic central nervous system injury in recent years, its research achievements and limitations, prospect the future development, and provide personal suggestions.  METHODS: CNKI, WanFang, PubMed, and Web of Science databases were searched for relevant articles using “adipose, mesenchymal stem cells, exosomes, traumatic central nervous system injury, spinal cord injury, traumatic brain injury, pathology” as the search terms in Chinese and English. Totally 42 articles that met the criteria were included for review.   RESULTS AND CONCLUSION: (1) By summarizing relevant literature conclusions, adipose-derived mesenchymal stem cell exosomes are used to treat traumatic central nervous system injury through the following mechanisms: inhibiting inflammation in the injured area through nuclear factor-kB, MAPK and other pathways, inhibiting neuronal apoptosis through JNK3/c-jun, SRSF2-PKCδII-Bcl2 pathways, and promoting nerve regeneration through cAMP-response element binding protein, neurofilament protein, growth-associated protein 43, glial fibrillary acidic protein, and myelin basic protein pathways. (2) Existing problems: the above research results are from preclinical experiments. The neuroprotective effect of miR-133b overexpressed in adipose mesenchymal stem cells in this paper is inconsistent with the conclusions of other studies, and needs further verification. Adipose-derived mesenchymal stem cell exosomes may have the risk of obesity and cerebral hemorrhage in the field of traumatic central nervous system injury, and their safety needs further study. The biological components and therapeutic mechanisms of adipose derived mesenchymal stem cell exosomes are not well explored. At present, there is no unified consensus on the standardized preparation, storage, transportation and administration strategies (including time, route and dose) of adipose mesenchymal stem cell exosomes. (3) In conclusion, adipose derived stem cell exosomes have a great application potential in traumatic central nervous system injury. Preclinical research in this field should be strengthened and gradually transferred to clinical research, so as to provide a new treatment for traumatic central nervous system injury.  Figures and Tables | References | Related Articles | Metrics

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Mechanism of Rehmannia glutinosa combined with mesenchymal stem cells in treating ischemic stroke Wei Zhihui, Liu Feixiang, Pan Xiaolong, Sun Shibiao, Zhang Yunke 2023, 27 (19):  3070-3076.  doi: 10.12307/2023.659 Abstract ( 233 )   PDF (1614KB) ( 128 )   Save BACKGROUND: Rehmannia glutinosa has the effects of inhibiting oxidative stress, inhibiting apoptosis, inhibiting nerve inflammation, promoting angiogenesis and anti-aging, and has unique advantages in the treatment of ischemic stroke. The combination of Rehmannia glutinosa with mesenchymal stem cells as a carrier can play a better role in the treatment of ischemic stroke.   OBJECTIVE: To review the research progress of Rehmannia glutinosa combined with mesenchymal stem cells in the treatment of ischemic stroke. METHODS: We searched CNKI and PubMed for the literature on the treatment of senile ischemic stroke with Rehmannia glutinosa combined with mesenchymal stem cells from 2012 to 2022. The keywords were “Rehmannia, mesenchymal stem cells (MSCs), ischemic stroke” in Chinese and English, respectively. Finally, 86 articles were included for further review.   RESULTS AND CONCLUSION: (1) The mechanisms of mesenchymal stem cells in the treatment of ischemic stroke were reviewed, including the promotion of cell migration and differentiation, immunomodulation, and inhibition of apoptosis. (2) The mechanisms of Rehmannia glutinosa in treating ischemic stroke were summarized, including inhibition of oxidative stress, inhibition of nerve inflammation, inhibition of apoptosis, promotion of neuroangiogenesis, and anti-aging. (3) Rehmannia glutinosa could stimulate the vitality of mesenchymal stem cells, promote the proliferation of mesenchymal stem cells, induce the differentiation of mesenchymal stem cells into neuron-like cells, and improve the survival rate of mesenchymal stem cells in vivo, so as to achieve the goal of synergistic treatment of ischemic stroke. (4) The mechanism of Rehmannia glutinosa combined with mesenchymal stem cells in the treatment of ischemic stroke was summarized, including inhibition of oxidative stress, inhibition of apoptosis, anti-aging, promotion of angiogenesis and nerve remodeling, thereby providing theoretical reference for the new treatment of ischemic stroke in the future. Figures and Tables | References | Related Articles | Metrics

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Effects and advantages of gingival mesenchymal stem cells in tissue regeneration Cheng Jingyuan, Liu Yue, Jiang Shaoyun 2023, 27 (19):  3077-3082.  doi: 10.12307/2023.657 Abstract ( 299 )   PDF (1683KB) ( 32 )   Save BACKGROUND: Gingiva is one of key components in periodontal complex, which is characterized by wound healing without scar. Gingival mesenchymal stem cells have multi-directional differentiation potential. In recent years, more and more studies have demonstrated that Gingival mesenchymal stem cells can be applied in the regeneration of certain tissues.   OBJECTIVE: To review the researches of gingival mesenchymal stem cells in tissue regeneration. METHODS: Retrieval of related-articles in nearly 20 years was conducted via China Biology Medicine (CBM), CNKI, PubMed databases. The search terms included “gingiva, mesenchymal stem cells, stem cell, regeneration, tissue, scaffold”. After preliminary screening through reading titles and abstracts to exclude the articles that were not related to the topic, 60 articles were finally included for further analysis.   RESULTS AND CONCLUSION: (1) Gingival mesenchymal stem cells can be differentiated into osteoblasts, chondroblasts, lipoblasts, endothelial cells, auditory cells and taste bud cells under certain induction conditions in vitro. (2) The combination of gingival mesenchymal stem cells and scaffolds such as alginate 3D scaffolds, 3D-printed polylactic acid scaffolds and 3D collagen scaffolds, can enhance the tissue regeneration potential. (3) Bioactive factors such as dexamethasone, bone-specific growth factor and insulin-like growth factor, can also enhance the regenerative potential. (4) However, the current construction and preparation of scaffold to delivery gingival mesenchymal stem cells are not ideal such as low survival rate and differentiation rate. Future research should focus on how to improve the efficiency of scaffold in order to apply gingival mesenchymal stem cells to regenerate tissue in clinic. Figures and Tables | References | Related Articles | Metrics

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Roles of Distal-less homeobox genes in osteogenic differentiation of odontogenic cells Zeng Manman, Tan Huaimei, Liu Yan 2023, 27 (19):  3083-3090.  doi: 10.12307/2023.666 Abstract ( 262 )   PDF (1646KB) ( 278 )   Save BACKGROUND: Recent studies have revealed that Distal-less(Dlx) homeobox genes play an important role in the induction of osteogenic differentiation of odontogenic cells and can participate in the regulation of various osteogenic-related signaling pathways or affect the expression of key osteogenic transcription factors. The regulatory effects of Dlx genes may provide new ideas and methods for clinical periodontal tissue regeneration studies.   OBJECTIVE: To review research progress on the role and mechanisms of the Dlx gene family in the osteogenic differentiation of odontogenic cells. METHODS: Literature retrieval was conducted in PubMed, CNKI, and WanFang databases. The search terms were “distal-less homeobox gene, distal-less homeobox,  Dlx, Dlx gene, bone-formation, osteogenesis, bone formation, ossification, ossifications, osteoclastogenesis, osteoclastogeneses, endochondral ossification, dental,oral, odontogenic, dental stem cell” in English and Chinese, respectively. Studies of low quality and irrelevant to the topic of the article were excluded. Finally, the included 82 articles were read, analyzed and summarized.   RESULTS AND CONCLUSION: (1) Homeobox genes are important genes that determine the growth and development of the body. Homeobox genes are composed of many families. Among them, the important osteogenic gene family is the Dlx gene family. The development of tooth germ is mainly related to two homeobox genes: MSX gene family and Dlx gene family. The latter plays an important role in the development of tooth germ and the differentiation of odontogenic cells. (2) The positive and negative feedback regulation of Dlx3 gene on BMP and Notch signaling pathway, and the osteogenic induction mechanism of Dlx3 gene overexpression on transcription factors zbtb16 and EGR1 are clarified. (3) Dlx2/3/5 can affect osteogenesis in dental follicle cells, which may be due to similar homologous domain external structure and chromosome localization. (4) Exploring the effects of of Dlx genes on dental tissues revealed that these complex molecular signaling and cell-cell ordering interactions involve the disturbance of the behavior of neural crest mesenchymal or its connective tissue matrix, resulting in many abnormalities of oral tooth morphology and maxillofacial bone. Therefore, all kinds of odontogenic transcription factors need to be strictly regulated in time and space and in their quantitative output. (5) Studies have confirmed the mechanism of Dlx gene family in the osteogenic differentiation of osteoblasts, chondroblasts and mesenchymal stem cells. With the continuous development of technology and in-depth research, the regulation and molecular signal mechanism of Dlx gene family on osteogenic differentiation of odontogenic cells will be further clarified. Figures and Tables | References | Related Articles | Metrics

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Clinical therapeutic prospect and current research status of stem cells for liver diseases Huang Guicai, Luo Yehao, Jiang Huirong, Li Yuan, Mao Dewen, Guan Zhijie 2023, 27 (19):  3091-3098.  doi: 10.12307/2023.633 Abstract ( 252 )   PDF (1858KB) ( 89 )   Save BACKGROUND: Stem cells play an important role in liver regeneration and self-repair ability, which is of great significance for clinical diagnosis and treatment of liver diseases.   OBJECTIVE: To summarize the current clinical trials and basic research in this field in and outside China, review the types of stem cells used to treat liver diseases in the past, and the treatment programs of various types of stem cells for various types of liver diseases, outline the clinical application prospects of various types of stem cells in the future application of liver diseases, and provide a research basis for the treatment of clinical liver diseases. METHODS: Using “stem cells, mesenchymal stem cells, hepatic stem cell, embryonic stem cell, induced pluripotent stem cell, hematopoietic stem cell, hepatopathy, non-alcoholic fatty liver disease, liver cirrhosis, liver failure, autoimmune hepatitis, hepatocellular carcinoma” as search words, the relevant articles in PubMed, Web of Science and Wiley e-journal databases were searched, and 71 articles were selected for review according to the inclusion criteria.   RESULTS AND CONCLUSION: (1) Mesenchymal stem cells, liver stem cells, embryonic stem cells, induced pluripotent stem cells and hematopoietic stem cells are the main stem cells for the treatment of liver diseases. The characteristics, expression period and application of these stem cells in differentiation after liver injury are summarized in this paper. (2) In general, mesenchymal stem cells can repair liver through exosomes, matrix metalloproteinase and anti-inflammatory response. Liver stem cells can differentiate liver oval cells and small hepatocellular progenitor cells to form mature liver cells and promote liver injury repair.  Induced pluripotent stem cells, embryonic stem cells and hematopoietic stem cells can transform into mature hepatocytes through rapid proliferation and differentiation. (3) The treatment of various liver diseases by stem cells is mainly achieved by inducing endogenous cell proliferation, immune regulation, inhibiting inflammation, promoting liver cell regeneration and repairing damaged tissues. (4) On the whole, at present, mesenchymal stem cells are relatively easy to obtain, have the broadest application prospects, and do not involve ethical issues. They are transforming from preclinical research to clinical research. Because mesenchymal stem cells can differentiate into various adult stem cells, they have the advantages of low immunogenicity, strong self-proliferation and differentiation ability. Especially for the treatment of immune hepatitis, liver cirrhosis and hepatocellular carcinoma and other liver diseases, mesenchymal stem cells have the most ideal effect. (5) Induced pluripotent stem cells are more effective in the treatment of end-stage liver disease because they can differentiate into specific somatic cells and hepatocytes without immune rejection. (6) However, stem cell transplantation can induce acute rejection, such as diarrhea, jaundice, and skin rashes. Poor histocompatibility between donors and recipients can easily lead to adverse reactions such as graft-versus-host reactions. After stem cell transplantation, the use of stem cells and its clinical safety assessment still need the support of more clinical trials and evidence-based medicine data. Figures and Tables | References | Related Articles | Metrics

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Different transplantation routes of mesenchymal stem cells can affect therapeutic effect on liver fibrosis Ma Gang, Zheng Xiaohong, Wang Jingbo, Han Ying 2023, 27 (19):  3099-3107.  doi: 10.12307/2023.345 Abstract ( 196 )   PDF (1754KB) ( 23 )   Save BACKGROUND: Mesenchymal stem cell transplantation is a promising new therapy for liver fibrosis, and the treatment effects are affected by many factors. The delivery route of mesenchymal stem cells is a key link in the treatment of liver fibrosis. There is controversy in the selection of the best transplantation route. The transplantation routes are particularly important to improve the treatment effects of mesenchymal stem cells. OBJECTIVE: To investigate the treatment effects of mesenchymal stem cells in the treatment of liver fibrosis by different transplantation routes. METHODS: Relevant articles from 2007 to 2021 in PubMed, CNKI, Wanfang and VIP databases were searched. The key words were “mesenchymal stem cells/stromal cells, liver/hepatic fibrosis/ cirrhosis, mechanism, distribution/biodistribution, transplantation route/delivery/engraftment/injection/administration” in Chinese and English, respectively. Repetitive, outdated and irrelevant views were excluded, and the 73 eligible articles were summarized and analyzed. RESULTS AND CONCLUSION: (1) In the same conditions, the biodistributions of liver mesenchymal stem cells in different transplantation routes were different, and different anti-fibrotic mechanisms may play an important role in improving liver fibrosis in different niches, thus, exerting different treatment effects on fibrosis. (2) Animal experiments have shown that the effects of mesenchymal stem cell transplantation for treating liver fibrosis via intraportal vein are equivalent to that of intrahepatic artery and not inferior to that of intravenous vein, which is higher than intrahepatic and intraperitioneal effects. (3) Clinical studies have shown that intrahepatic and intrasplenic routes have similar treatment effects; intrahepatic artery and intraportal vein have the same effects and superior to the intravenous transplantation. (4) The routes via intrahepatic artery and intraportal vein may be the best way to treat liver fibrosis, and intrahepatic and intrasplenic routes may limit the therapeutic effects of stem cells because of “Cell crowding” and “Transient clearance”. (5) The transplantation routes of mesenchymal stem cells are safe and effective in the treatment of liver fibrosis. It may be beneficial to improve the treatment effects of mesenchymal stem cells to select appropriate approaches to increase stem cell colonization, enhance cell activity, and maintain the survival time of stem cells in liver tissue. It may be beneficial to improve the anti-fibrotic effect of mesenchymal stem cells, but the mechanisms of different transplantation routes are not so far clear, and the indications of different routes need to be further explored. Figures and Tables | References | Related Articles | Metrics

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A new direction in tissue engineering technology for the treatment of ischemic heart disease Qiang Yongjia, Zeng Kuan, Zhang Bin, Guan Ruicong, Liu Zhuxuan, Xu Haohua, Zhang Xinyi, Yang Yanqi 2023, 27 (19):  3108-3116.  doi: 10.12307/2023.655 Abstract ( 285 )   PDF (1662KB) ( 101 )   Save BACKGROUND: Stem cell therapy is a hot spot and has been applied in various clinical disciplines at present, but it has little effect in the treatment of ischemic heart disease, mainly because the survival rate of stem cells transplanted into ischemic myocardium is very low. The discovery and application of new tissue engineering materials help to improve the survival rate of human mesenchymal stem cells in ischemic myocardium, which makes people see the broad application prospect of human mesenchymal stem cells in the treatment of ischemic myocardium.   OBJECTIVE: To summarize the research progress of three kinds of common tissue engineering scaffolds in stem cell therapy for ischemic heart disease and put forward the future application prospects. METHODS: PubMed and Web of Science databases were used. The English search words were “mesenchymal stem cells, biological hydrogel nanometer material, 3D printing, nanostructured material”. CNKI, Wanfang, and VIP databases were applied, and the Chinese keywords were “stem cells, ischemic heart disease, tissue engineering, hydrogel, 3D printing, nano materials”. Relevant articles on tissue engineering technology in the treatment of ischemic heart disease from 2010 to 2021 were retrieved, excluding duplicate studies, case reports or meta-analysis articles, and finally 74 articles meeting the criteria were included for review.   RESULTS AND CONCLUSION: (1) There are many kinds of gelatin gel substrate materials and preparation technologies available. It is also the most mature tissue engineering scaffold material and the most promising scaffold material for carrying stem cells to treat ischemic heart disease in the future. (2) Nano materials have unique physical and chemical properties. Scaffolds constructed with nano materials can not only promote the survival and proliferation of human mesenchymal stem cells in ischemic myocardium, but also make human mesenchymal stem cells well play its paracrine role, thus it plays a role in the treatment of myocardial ischemia. (3) The emerging 3D printing technology can use hydrogels, nano materials, and stem cells as raw materials to print the required cells, blood vessels, myocardium, ventricles, atria, and even “complete” hearts, but it still needs further development from clinical application. (4) In terms of future prospects, a large number of in vitro tissue and cell experiments help to establish a more perfect scaffold system and find the most suitable extracellular matrix environment for the survival of human mesenchymal stem cells. The construction of a standardized animal model of myocardial ischemia is conducive to in-depth understanding of the physiological performance of stem cells in different scaffold materials in basic research, and clinical application needs the support of animal experimental data from multiple centers and large samples in the future. Figures and Tables | References | Related Articles | Metrics