Exploring the mechanism of self-renewal and pluripotency maintenance of human embryonic stem cells (hESCs) is of great significance in basic research and clinical applications, but it has not been fully elucidated. Long non-coding RNAs (lncRNAs) have been shown to play a key role in the self-renewal and pluripotency maintenance of hESCs. We previously reported that the lncRNA ESRG, which is highly expressed in undifferentiated hESCs, can maintain the self-renewal and pluripotency of hPSCs. RNA pull-down mass spectrometry showed that ESRG could bind to other proteins, among which heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1) attracted our attention. In this study, we showed that HNRNPA1 can maintain self-renewal and pluripotency of hESCs. ESRG bound to and stabilized HNRNPA1 protein through the ubiquitin-proteasome pathway. In addition, knockdown of ESRG or HNRNPA1 resulted in alternative splicing of TCF3, which originally and primarily encoded E12, to mainly encode E47 and inhibit CDH1 expression. HNRNPA1 could rescue the biological function changes of hESCs caused by ESRG knockdown or overexpression. Our results suggest that ESRG regulates the alternative splicing of TCF3 to affect CDH1 expression and maintain hESCs self-renewal and pluripotency by binding and stabilizing HNRNPA1 protein. This study lays a good foundation for exploring the new molecular regulatory mechanism by which ESRG maintains hESCs self-renewal and pluripotency.
{"title":"Embryonic stem cell related gene regulates alternative splicing of transcription factor 3 to maintain human embryonic stem cells' self-renewal and pluripotency.","authors":"Wen Xie, Weidong Liu, Lei Wang, Shasha Li, Zilin Liao, Hongjuan Xu, Yihan Li, Xingjun Jiang, Caiping Ren","doi":"10.1093/stmcls/sxae020","DOIUrl":"10.1093/stmcls/sxae020","url":null,"abstract":"<p><p>Exploring the mechanism of self-renewal and pluripotency maintenance of human embryonic stem cells (hESCs) is of great significance in basic research and clinical applications, but it has not been fully elucidated. Long non-coding RNAs (lncRNAs) have been shown to play a key role in the self-renewal and pluripotency maintenance of hESCs. We previously reported that the lncRNA ESRG, which is highly expressed in undifferentiated hESCs, can maintain the self-renewal and pluripotency of hPSCs. RNA pull-down mass spectrometry showed that ESRG could bind to other proteins, among which heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1) attracted our attention. In this study, we showed that HNRNPA1 can maintain self-renewal and pluripotency of hESCs. ESRG bound to and stabilized HNRNPA1 protein through the ubiquitin-proteasome pathway. In addition, knockdown of ESRG or HNRNPA1 resulted in alternative splicing of TCF3, which originally and primarily encoded E12, to mainly encode E47 and inhibit CDH1 expression. HNRNPA1 could rescue the biological function changes of hESCs caused by ESRG knockdown or overexpression. Our results suggest that ESRG regulates the alternative splicing of TCF3 to affect CDH1 expression and maintain hESCs self-renewal and pluripotency by binding and stabilizing HNRNPA1 protein. This study lays a good foundation for exploring the new molecular regulatory mechanism by which ESRG maintains hESCs self-renewal and pluripotency.</p>","PeriodicalId":231,"journal":{"name":"STEM CELLS","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139929260","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Abel Soto-Gamez, Jeremy P Gunawan, Lara Barazzuol, Sarah Pringle, Rob P Coppes
Inter-individual variation largely influences disease susceptibility, as well as response to therapy. In a clinical context, the optimal treatment of a disease should consider inter-individual variation and formulate tailored decisions at an individual level. In recent years, emerging organoid technologies promise to capture part of an individual's phenotypic variability and prove helpful in providing clinically relevant molecular insights. Organoids are stem cell-derived 3-dimensional models that contain multiple cell types that can self-organize and give rise to complex structures mimicking the organization and functionality of the tissue of origin. Organoids therefore represent a more faithful recapitulation of the dynamics of the tissues of interest, compared to conventional monolayer cultures, thus supporting their use in evaluating disease prognosis, or as a tool to predict treatment outcomes. Additionally, the individualized nature of patient-derived organoids enables the use of autologous organoids as a source of transplantable material not limited by histocompatibility. An increasing amount of preclinical evidence has paved the way for clinical trials exploring the applications of organoid-based technologies, some of which are in phase I/II. This review focuses on the recent progress concerning the use of patient-derived organoids in personalized medicine, including (1) diagnostics and disease prognosis, (2) treatment outcome prediction to guide therapeutic advice, and (3) organoid transplantation or cell-based therapies. We discuss examples of these potential applications and the challenges associated with their future implementation.
{"title":"Organoid-based personalized medicine: from tumor outcome prediction to autologous transplantation.","authors":"Abel Soto-Gamez, Jeremy P Gunawan, Lara Barazzuol, Sarah Pringle, Rob P Coppes","doi":"10.1093/stmcls/sxae023","DOIUrl":"10.1093/stmcls/sxae023","url":null,"abstract":"<p><p>Inter-individual variation largely influences disease susceptibility, as well as response to therapy. In a clinical context, the optimal treatment of a disease should consider inter-individual variation and formulate tailored decisions at an individual level. In recent years, emerging organoid technologies promise to capture part of an individual's phenotypic variability and prove helpful in providing clinically relevant molecular insights. Organoids are stem cell-derived 3-dimensional models that contain multiple cell types that can self-organize and give rise to complex structures mimicking the organization and functionality of the tissue of origin. Organoids therefore represent a more faithful recapitulation of the dynamics of the tissues of interest, compared to conventional monolayer cultures, thus supporting their use in evaluating disease prognosis, or as a tool to predict treatment outcomes. Additionally, the individualized nature of patient-derived organoids enables the use of autologous organoids as a source of transplantable material not limited by histocompatibility. An increasing amount of preclinical evidence has paved the way for clinical trials exploring the applications of organoid-based technologies, some of which are in phase I/II. This review focuses on the recent progress concerning the use of patient-derived organoids in personalized medicine, including (1) diagnostics and disease prognosis, (2) treatment outcome prediction to guide therapeutic advice, and (3) organoid transplantation or cell-based therapies. We discuss examples of these potential applications and the challenges associated with their future implementation.</p>","PeriodicalId":231,"journal":{"name":"STEM CELLS","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11177156/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140206023","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
SIRT6 owns versatile types of enzymatic activities as a multitasking protein, including ribosyltransferase and deacetylase ones. To investigate the epigenetic regulations of SIRT6 on MSC fate determination via histone deacetylation, we utilized allosteric small molecules specifically controlling its histone 3 deacetylation activities. Results showed that enhanced deacetylation of SIRT6 promoted the ossific lineage commitment of MSC and finally achieved anabolic effects on hard tissues. Mechanistically, H3K9ac and H3K56ac, governed by SIRT6, in MSC orchestrated the transcriptions of crucial metabolic genes, mediating MSC fate determination. Most importantly, our data evidenced that modulating the epigenetic regulations of SIRT6, specifically via enhancing its deacetylation of H3K9ac and H3K56ac, was a promising choice to treat bone loss diseases and promote dentine regeneration. In this study, we revealed the specific roles of SIRT6's histone modification in MSC fate determination. These findings endow us with insights on SIRT6 and the promising therapeutic choices through SIRT6's epigenetic functions for hard tissues regeneration.
{"title":"Epigenetically Rewiring Metabolic Genes via SIRT6 Orchestrates MSC Fate Determination.","authors":"Xueyang Liao, Feifei Li, Fanyuan Yu, Ling Ye","doi":"10.1093/stmcls/sxae041","DOIUrl":"https://doi.org/10.1093/stmcls/sxae041","url":null,"abstract":"<p><p>SIRT6 owns versatile types of enzymatic activities as a multitasking protein, including ribosyltransferase and deacetylase ones. To investigate the epigenetic regulations of SIRT6 on MSC fate determination via histone deacetylation, we utilized allosteric small molecules specifically controlling its histone 3 deacetylation activities. Results showed that enhanced deacetylation of SIRT6 promoted the ossific lineage commitment of MSC and finally achieved anabolic effects on hard tissues. Mechanistically, H3K9ac and H3K56ac, governed by SIRT6, in MSC orchestrated the transcriptions of crucial metabolic genes, mediating MSC fate determination. Most importantly, our data evidenced that modulating the epigenetic regulations of SIRT6, specifically via enhancing its deacetylation of H3K9ac and H3K56ac, was a promising choice to treat bone loss diseases and promote dentine regeneration. In this study, we revealed the specific roles of SIRT6's histone modification in MSC fate determination. These findings endow us with insights on SIRT6 and the promising therapeutic choices through SIRT6's epigenetic functions for hard tissues regeneration.</p>","PeriodicalId":231,"journal":{"name":"STEM CELLS","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141305083","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cisplatin is widely employed in tumor chemotherapy, but nephrotoxicity is an unavoidable side effect of cisplatin. Several studies have demonstrated that mesenchymal stromal cells (MSCs) ameliorate cisplatin-induced kidney injury, but the underlying mechanisms are unknown. In this study, the cisplatin-induced kidney injury mouse model was established by subjecting a single intraperitoneal injection with cisplatin. One hour before cisplatin injection, the mice received human bone marrow MSCs (hBM-MSCs) with or without siRNA-transfection, recombinant human tumor necrosis factor (TNF)-α-stimulated gene/protein 6 (rhTSG-6), or PBS through tail vein. In addition, cisplatin-stimulated HK-2 cells were treated with hBM-MSCs or rhTSG-6. hBM-MSCs treatment remarkably ameliorated cisplatin-induced acute and chronic kidney injury, as evidenced by significant reductions in serum creatinine (Scr), blood urea nitrogen (BUN), tubular injury, collagen deposition, α-smooth muscle actin accumulation, as well as inflammatory responses, and by remarkable increased anti-inflammatory factor expression and Treg cells infiltration in renal tissues. Furthermore, we found that only a few hBM-MSCs engrafted into damaged kidney and that the level of human TSG-6 in serum of mice increased significantly following hBM-MSCs administration. Moreover, hBM-MSCs significantly increased the viability of damaged HK-2 cells and decreased the levels of inflammatory cytokines in the culture supernatant. However, knockdown of TSG-6 gene in hBM-MSCs significantly attenuated their beneficial effects in vivo and in vitro. On the contrary, treated with rhTSG-6 achieved similar beneficial effects of hBM-MSCs. Our results indicate that systemic administration of hBM-MSCs alleviate cisplatin-induced acute and chronic kidney injury in part by paracrine TSG-6 secretion.
{"title":"Human mesenchymal stromal cells ameliorate cisplatin induced acute and chronic kidney injury via TSG-6.","authors":"Ming Tang, Linguo Shen, Maozhi Tang, Ling Liu, Zhengsheng Rao, Zhilin Wang, Yadi Wang, Supei Yin, Shujing Li, Guilian Xu, Keqin Zhang","doi":"10.1093/stmcls/sxae037","DOIUrl":"https://doi.org/10.1093/stmcls/sxae037","url":null,"abstract":"<p><p>Cisplatin is widely employed in tumor chemotherapy, but nephrotoxicity is an unavoidable side effect of cisplatin. Several studies have demonstrated that mesenchymal stromal cells (MSCs) ameliorate cisplatin-induced kidney injury, but the underlying mechanisms are unknown. In this study, the cisplatin-induced kidney injury mouse model was established by subjecting a single intraperitoneal injection with cisplatin. One hour before cisplatin injection, the mice received human bone marrow MSCs (hBM-MSCs) with or without siRNA-transfection, recombinant human tumor necrosis factor (TNF)-α-stimulated gene/protein 6 (rhTSG-6), or PBS through tail vein. In addition, cisplatin-stimulated HK-2 cells were treated with hBM-MSCs or rhTSG-6. hBM-MSCs treatment remarkably ameliorated cisplatin-induced acute and chronic kidney injury, as evidenced by significant reductions in serum creatinine (Scr), blood urea nitrogen (BUN), tubular injury, collagen deposition, α-smooth muscle actin accumulation, as well as inflammatory responses, and by remarkable increased anti-inflammatory factor expression and Treg cells infiltration in renal tissues. Furthermore, we found that only a few hBM-MSCs engrafted into damaged kidney and that the level of human TSG-6 in serum of mice increased significantly following hBM-MSCs administration. Moreover, hBM-MSCs significantly increased the viability of damaged HK-2 cells and decreased the levels of inflammatory cytokines in the culture supernatant. However, knockdown of TSG-6 gene in hBM-MSCs significantly attenuated their beneficial effects in vivo and in vitro. On the contrary, treated with rhTSG-6 achieved similar beneficial effects of hBM-MSCs. Our results indicate that systemic administration of hBM-MSCs alleviate cisplatin-induced acute and chronic kidney injury in part by paracrine TSG-6 secretion.</p>","PeriodicalId":231,"journal":{"name":"STEM CELLS","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141157261","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Li-Tzu Wang, Wei Lee, Ko-Jiunn Liu, Huey-Kang Sytwu, Men-Luh Yen, B Linju Yen
Polymorphonuclear neutrophils (PMNs), the predominant immune cell type in humans, have long been known as first-line effector cells against bacterial infections mainly through phagocytosis and production of reactive oxygen species (ROS). However, recent research has unveiled novel and pivotal roles of these abundant but short-lived granulocytes in health and disease. Human mesenchymal stromal/stem cells (MSCs), renowned for their regenerative properties and modulation of T lymphocytes from effector to regulatory phenotypes, exhibit complex and context-dependent interactions with PMNs. Regardless of species or source, MSCs strongly abrogate PMN apoptosis, a critical determinant of PMN function, except if PMNs are highly stimulated. MSCs also have the capacity to fine-tune PMN activation, particularly in terms of CD11b expression and phagocytosis. Moreover, MSCs can modulate numerous other PMN functions, spanning migration, ROS production, and neutrophil extracellular trap (NET) formation/NETosis, but directionality is remarkably dependent on the underlying context: in normal nondiseased conditions, MSCs enhance PMN migration and ROS production, whereas in inflammatory conditions, MSCs reduce both these functions and NETosis. Furthermore, the state of the MSCs themselves, whether isolated from diseased or healthy donors, and the specific secreted products and molecules, can impact interactions with PMNs; while healthy MSCs prevent PMN infiltration and NETosis, MSCs isolated from patients with cancer promote these functions. This comprehensive analysis highlights the intricate interplay between PMNs and MSCs and its profound relevance in healthy and pathological conditions, shedding light on how to best strategize the use of MSCs in the expanding list of diseases with PMN involvement.
{"title":"Mesenchymal Stromal/Stem Cells Know Best: The Remarkable Complexities of Its Interactions With Polymorphonuclear Neutrophils.","authors":"Li-Tzu Wang, Wei Lee, Ko-Jiunn Liu, Huey-Kang Sytwu, Men-Luh Yen, B Linju Yen","doi":"10.1093/stmcls/sxae011","DOIUrl":"10.1093/stmcls/sxae011","url":null,"abstract":"<p><p>Polymorphonuclear neutrophils (PMNs), the predominant immune cell type in humans, have long been known as first-line effector cells against bacterial infections mainly through phagocytosis and production of reactive oxygen species (ROS). However, recent research has unveiled novel and pivotal roles of these abundant but short-lived granulocytes in health and disease. Human mesenchymal stromal/stem cells (MSCs), renowned for their regenerative properties and modulation of T lymphocytes from effector to regulatory phenotypes, exhibit complex and context-dependent interactions with PMNs. Regardless of species or source, MSCs strongly abrogate PMN apoptosis, a critical determinant of PMN function, except if PMNs are highly stimulated. MSCs also have the capacity to fine-tune PMN activation, particularly in terms of CD11b expression and phagocytosis. Moreover, MSCs can modulate numerous other PMN functions, spanning migration, ROS production, and neutrophil extracellular trap (NET) formation/NETosis, but directionality is remarkably dependent on the underlying context: in normal nondiseased conditions, MSCs enhance PMN migration and ROS production, whereas in inflammatory conditions, MSCs reduce both these functions and NETosis. Furthermore, the state of the MSCs themselves, whether isolated from diseased or healthy donors, and the specific secreted products and molecules, can impact interactions with PMNs; while healthy MSCs prevent PMN infiltration and NETosis, MSCs isolated from patients with cancer promote these functions. This comprehensive analysis highlights the intricate interplay between PMNs and MSCs and its profound relevance in healthy and pathological conditions, shedding light on how to best strategize the use of MSCs in the expanding list of diseases with PMN involvement.</p>","PeriodicalId":231,"journal":{"name":"STEM CELLS","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139680447","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cellular senescence significantly affects the proliferative and differentiation capacities of mesenchymal stem cells (MSCs). Identifying key regulators of senescence and exploring potential intervention strategies, including drug-based approaches, are active areas of research. In this context, S-adenosyl-l-methionine (SAM), a critical intermediate in sulfur amino acid metabolism, emerges as a promising candidate for mitigating MSC senescence. In a hydrogen peroxide-induced MSC aging model (100 μM for 2 hours), SAM (50 and 100 μM) was revealed to alleviate the senescence of MSCs, and also attenuated the level of reactive oxygen species and enhanced the adipogenic and osteogenic differentiation in senescent MSCs. In a premature aging mouse model (subcutaneously injected with 150 mg/kg/day d-galactose in the neck and back for 7 weeks), SAM (30 mg/kg/day by gavage for 5 weeks) was shown to delay the overall aging process while increasing the number and thickness of bone trabeculae in the distal femur. Mechanistically, activation of PI3K/AKT signaling and increased phosphorylation of forkhead box O3 (FOXO3a) was proved to be associated with the antisenescence role of SAM. These findings highlight that the PI3K/AKT/FOXO3a axis in MSCs could play a crucial role in MSCs senescence and suggest that SAM may be a potential therapeutic drug for MSCs senescence and related diseases.
{"title":"S-Adenosyl-l-Methionine Alleviates the Senescence of MSCs Through the PI3K/AKT/FOXO3a Signaling Pathway.","authors":"Lipeng Shang, Xiaoxia Li, Xiaoyan Ding, Guoxiang Liu, Zhen Pan, Xiangyan Chen, Yuelei Wang, Bing Li, Ting Wang, Robert Chunhua Zhao","doi":"10.1093/stmcls/sxae010","DOIUrl":"10.1093/stmcls/sxae010","url":null,"abstract":"<p><p>Cellular senescence significantly affects the proliferative and differentiation capacities of mesenchymal stem cells (MSCs). Identifying key regulators of senescence and exploring potential intervention strategies, including drug-based approaches, are active areas of research. In this context, S-adenosyl-l-methionine (SAM), a critical intermediate in sulfur amino acid metabolism, emerges as a promising candidate for mitigating MSC senescence. In a hydrogen peroxide-induced MSC aging model (100 μM for 2 hours), SAM (50 and 100 μM) was revealed to alleviate the senescence of MSCs, and also attenuated the level of reactive oxygen species and enhanced the adipogenic and osteogenic differentiation in senescent MSCs. In a premature aging mouse model (subcutaneously injected with 150 mg/kg/day d-galactose in the neck and back for 7 weeks), SAM (30 mg/kg/day by gavage for 5 weeks) was shown to delay the overall aging process while increasing the number and thickness of bone trabeculae in the distal femur. Mechanistically, activation of PI3K/AKT signaling and increased phosphorylation of forkhead box O3 (FOXO3a) was proved to be associated with the antisenescence role of SAM. These findings highlight that the PI3K/AKT/FOXO3a axis in MSCs could play a crucial role in MSCs senescence and suggest that SAM may be a potential therapeutic drug for MSCs senescence and related diseases.</p>","PeriodicalId":231,"journal":{"name":"STEM CELLS","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140011787","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jian Chen, Yaqiong Zhu, Hui Gao, Xianghui Chen, Dan Yi, MoLin Li, Li Wang, Guanhui Xing, Siming Chen, Jie Tang, Yuexiang Wang
Cell therapy based on mesenchymal stem cells (MSCs) alleviate muscle atrophy caused by diabetes and aging; however, the impact of human umbilical cord mesenchymal stem cells on muscle atrophy following nerve injury and the underlying mechanisms remain unclear. In this study, we evaluated the therapeutic efficacy of human umbilical cord MSCs (hucMSCs) and hucMSC-derived exosomes (hucMSC-EXOs) for muscle atrophy following nerve injury and identified the underlying molecular mechanisms. Sciatic nerve crush injury in rats and the induction of myotubes in L6 cells were used to determine the ameliorating effect of hucMSCs and hucMSC-EXOs on muscle atrophy. Q-PCR and Western blot analyses were used to measure the expression of muscle-specific ubiquitin ligases Fbxo32 (Atrogin1, MAFbx) and Trim63 (MuRF-1). Dual-luciferase reporter gene experiments were conducted to validate the direct binding of miRNAs to their target genes. Local injection of hucMSCs and hucMSC-EXOs mitigated atrophy in the rat gastrocnemius muscle following sciatic nerve crush injury. In vitro, hucMSC-EXOs alleviated atrophy in L6 myotubes. Mechanistic analysis indicated the upregulation of miR-23b-3p levels in L6 myotubes following hucMSC-EXOs treatment. MiR-23b-3p significantly inhibited the expression of its target genes, Fbxo32 and Trim63, and suppressed myotube atrophy. Notably, an miR-23b-3p inhibitor reversed the inhibitory effect of miR-23b-3p on myotube atrophy in vitro. These results suggest that hucMSCs and their exosomes alleviate muscle atrophy following nerve injury. MiR-23b-3p in exosomes secreted by hucMSCs contributes to this mechanism by inhibiting the muscle-specific ubiquitination ligases Fbxo32 and Trim63.
{"title":"HucMSCs Delay Muscle Atrophy After Peripheral Nerve Injury Through Exosomes by Repressing Muscle-Specific Ubiquitin Ligases.","authors":"Jian Chen, Yaqiong Zhu, Hui Gao, Xianghui Chen, Dan Yi, MoLin Li, Li Wang, Guanhui Xing, Siming Chen, Jie Tang, Yuexiang Wang","doi":"10.1093/stmcls/sxae017","DOIUrl":"10.1093/stmcls/sxae017","url":null,"abstract":"<p><p>Cell therapy based on mesenchymal stem cells (MSCs) alleviate muscle atrophy caused by diabetes and aging; however, the impact of human umbilical cord mesenchymal stem cells on muscle atrophy following nerve injury and the underlying mechanisms remain unclear. In this study, we evaluated the therapeutic efficacy of human umbilical cord MSCs (hucMSCs) and hucMSC-derived exosomes (hucMSC-EXOs) for muscle atrophy following nerve injury and identified the underlying molecular mechanisms. Sciatic nerve crush injury in rats and the induction of myotubes in L6 cells were used to determine the ameliorating effect of hucMSCs and hucMSC-EXOs on muscle atrophy. Q-PCR and Western blot analyses were used to measure the expression of muscle-specific ubiquitin ligases Fbxo32 (Atrogin1, MAFbx) and Trim63 (MuRF-1). Dual-luciferase reporter gene experiments were conducted to validate the direct binding of miRNAs to their target genes. Local injection of hucMSCs and hucMSC-EXOs mitigated atrophy in the rat gastrocnemius muscle following sciatic nerve crush injury. In vitro, hucMSC-EXOs alleviated atrophy in L6 myotubes. Mechanistic analysis indicated the upregulation of miR-23b-3p levels in L6 myotubes following hucMSC-EXOs treatment. MiR-23b-3p significantly inhibited the expression of its target genes, Fbxo32 and Trim63, and suppressed myotube atrophy. Notably, an miR-23b-3p inhibitor reversed the inhibitory effect of miR-23b-3p on myotube atrophy in vitro. These results suggest that hucMSCs and their exosomes alleviate muscle atrophy following nerve injury. MiR-23b-3p in exosomes secreted by hucMSCs contributes to this mechanism by inhibiting the muscle-specific ubiquitination ligases Fbxo32 and Trim63.</p>","PeriodicalId":231,"journal":{"name":"STEM CELLS","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11094387/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139929261","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Zexu Peng, Ana Ludke, Jun Wu, Shuhong Li, Faisal J Alibhai, Yichong Zhang, Yunfei Fan, Huifang Song, Sheng He, Jun Xie, Ren-Ke Li
It has been documented that the uterus plays a key cardio-protective role in pre-menopausal women, which is supported by uterine cell therapy, to preserve cardiac functioning post-myocardial infarction, being effective among females. However, whether such therapies would also be beneficial among males is still largely unknown. In this study, we aimed to fill in this gap in knowledge by examining the effects of transplanted uterine cells on infarcted male hearts. We identified, based on major histocompatibility complex class I (MHC-I) expression levels, 3 uterine reparative cell populations: MHC-I(neg), MHC-I(mix), and MHC-I(pos). In vitro, MHC-I(neg) cells showed higher levels of pro-angiogenic, pro-survival, and anti-inflammatory factors, compared to MHC-I(mix) and MHC-I(pos). Furthermore, when cocultured with allogeneic mixed leukocytes, MHC-I(neg) had lower cytotoxicity and leukocyte proliferation. In particular, CD8+ cytotoxic T cells significantly decreased, while CD4+CD25+ Tregs and CD4-CD8- double-negative T cells significantly increased when cocultured with MHC-I(neg), compared to MHC-I(mix) and MHC-I(pos) cocultures. In vivo, MHC-I(neg) as well as MHC-I(mix) were found under both syngeneic and allogeneic transplantation in infarcted male hearts, to significantly improve cardiac function and reduce the scar size, via promoting angiogenesis in the infarcted area. All of these findings thus support the view that males could also benefit from the cardio-protective effects observed among females, via cell therapy approaches involving the transplantation of immuno-privileged uterine reparative cells in infarcted hearts.
有资料表明,子宫对绝经前妇女的心脏起着关键的保护作用,而子宫细胞疗法对女性心肌梗塞(MI)后心脏功能的保护也证明了这一点。然而,这种疗法是否对男性也有益处在很大程度上仍是未知数。在这项研究中,我们旨在通过研究移植子宫细胞对梗死男性心脏的影响来填补这一知识空白。根据主要组织相容性复合体 I 类(MHC-I)的表达水平,我们确定了 3 种子宫修复细胞群:MHC-I(阴性)、MHC-I(混合)和MHC-I(阳性)。在体外,与 MHC-I(混合)和 MHC-I(阳性)相比,MHC-I(阴性)细胞显示出更高水平的促血管生成因子、促生存因子和抗炎因子。此外,当与异体混合白细胞共同培养时,MHC-I(阴性)细胞毒性和白细胞增殖能力较低。特别是,与 MHC-I(阴性)和 MHC-I(阳性)共培养相比,与 MHC-I(混合)共培养时,CD8+细胞毒性 T 细胞显著减少,而 CD4+CD25+ Tregs 和 CD4-CD8- 双阴性 T 细胞显著增加。在体内,研究发现 MHC-I(阴性)和 MHC-I(混合)通过促进梗死区域的血管生成,在同种异体移植男性梗死心脏的情况下都能明显改善心脏功能并缩小疤痕。因此,所有这些研究结果都支持这样一种观点,即通过在梗塞心脏移植免疫特异性子宫修复细胞的细胞疗法,男性也能受益于在女性中观察到的心脏保护效果。
{"title":"Uterine Immunoprivileged Cells Restore Cardiac Function of Male Recipients After Myocardial Infarction.","authors":"Zexu Peng, Ana Ludke, Jun Wu, Shuhong Li, Faisal J Alibhai, Yichong Zhang, Yunfei Fan, Huifang Song, Sheng He, Jun Xie, Ren-Ke Li","doi":"10.1093/stmcls/sxae008","DOIUrl":"10.1093/stmcls/sxae008","url":null,"abstract":"<p><p>It has been documented that the uterus plays a key cardio-protective role in pre-menopausal women, which is supported by uterine cell therapy, to preserve cardiac functioning post-myocardial infarction, being effective among females. However, whether such therapies would also be beneficial among males is still largely unknown. In this study, we aimed to fill in this gap in knowledge by examining the effects of transplanted uterine cells on infarcted male hearts. We identified, based on major histocompatibility complex class I (MHC-I) expression levels, 3 uterine reparative cell populations: MHC-I(neg), MHC-I(mix), and MHC-I(pos). In vitro, MHC-I(neg) cells showed higher levels of pro-angiogenic, pro-survival, and anti-inflammatory factors, compared to MHC-I(mix) and MHC-I(pos). Furthermore, when cocultured with allogeneic mixed leukocytes, MHC-I(neg) had lower cytotoxicity and leukocyte proliferation. In particular, CD8+ cytotoxic T cells significantly decreased, while CD4+CD25+ Tregs and CD4-CD8- double-negative T cells significantly increased when cocultured with MHC-I(neg), compared to MHC-I(mix) and MHC-I(pos) cocultures. In vivo, MHC-I(neg) as well as MHC-I(mix) were found under both syngeneic and allogeneic transplantation in infarcted male hearts, to significantly improve cardiac function and reduce the scar size, via promoting angiogenesis in the infarcted area. All of these findings thus support the view that males could also benefit from the cardio-protective effects observed among females, via cell therapy approaches involving the transplantation of immuno-privileged uterine reparative cells in infarcted hearts.</p>","PeriodicalId":231,"journal":{"name":"STEM CELLS","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139519411","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Boon Min Poh, Lee Chuen Liew, Yan Ni Annie Soh, Ruenn Chai Lai, Sai Kiang Lim, Ying Swan Ho, Boon Seng Soh
Cardiovascular diseases (CVDs) are the leading cause of death worldwide, accounting for 31% of all deaths globally. Myocardial ischemia-reperfusion injury (IRI), a common complication of CVDs, is a major cause of mortality and morbidity. Studies have shown efficacious use of mesenchymal stem cells-derived small extracellular vesicles (MSCs-EVs) to mitigate IRI in animals, but few research has been done on human-related models. In this study, human embryonic stem cell-derived chambered cardiac organoid (CCO) was used as a model system to study the effects of MSC-EVs on myocardial IRI. The results revealed that MSC-EVs treatment reduced apoptosis and improved contraction resumption of the CCOs. Metabolomics analysis showed that this effect could be attributed to EVs' ability to prevent the accumulation of unsaturated very long-chain fatty acids (VLCFAs). This was corroborated when inhibition of fatty acid synthase, which was reported to reduce VLCFAs, produced a similar protective effect to EVs. Overall, this study uncovered the mechanistic role of MSC-EVs in mitigating IRI that involves preventing the accumulation of unsaturated VLCFA, decreasing cell death, and improving contraction resumption in CCOs.
{"title":"MSC-Derived Small Extracellular Vesicles Exert Cardioprotective Effect Through Reducing VLCFAs and Apoptosis in Human Cardiac Organoid IRI Model.","authors":"Boon Min Poh, Lee Chuen Liew, Yan Ni Annie Soh, Ruenn Chai Lai, Sai Kiang Lim, Ying Swan Ho, Boon Seng Soh","doi":"10.1093/stmcls/sxae015","DOIUrl":"10.1093/stmcls/sxae015","url":null,"abstract":"<p><p>Cardiovascular diseases (CVDs) are the leading cause of death worldwide, accounting for 31% of all deaths globally. Myocardial ischemia-reperfusion injury (IRI), a common complication of CVDs, is a major cause of mortality and morbidity. Studies have shown efficacious use of mesenchymal stem cells-derived small extracellular vesicles (MSCs-EVs) to mitigate IRI in animals, but few research has been done on human-related models. In this study, human embryonic stem cell-derived chambered cardiac organoid (CCO) was used as a model system to study the effects of MSC-EVs on myocardial IRI. The results revealed that MSC-EVs treatment reduced apoptosis and improved contraction resumption of the CCOs. Metabolomics analysis showed that this effect could be attributed to EVs' ability to prevent the accumulation of unsaturated very long-chain fatty acids (VLCFAs). This was corroborated when inhibition of fatty acid synthase, which was reported to reduce VLCFAs, produced a similar protective effect to EVs. Overall, this study uncovered the mechanistic role of MSC-EVs in mitigating IRI that involves preventing the accumulation of unsaturated VLCFA, decreasing cell death, and improving contraction resumption in CCOs.</p>","PeriodicalId":231,"journal":{"name":"STEM CELLS","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139929262","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Xiaoli Yang, Meng Chen, Shuang Wang, Xingli Hu, Jie Zhou, Hairui Yuan, Endong Zhu, Baoli Wang
Cortactin, a cytoskeletal protein and substrate of src kinase, is implicated in tumor aggressiveness. However, its role in bone cell differentiation remains unknown. The current study revealed that cortactin was upregulated during osteoblast and adipocyte differentiation. Functional experiments demonstrated that cortactin promoted the differentiation of mesenchymal stem/progenitor cells into osteogenic and adipogenic lineages. Mechanistically, cortactin was able to stabilize the protein level of mechanistic target of rapamycin kinase (mTOR), leading to the activation of mTOR signaling. In-depth investigation revealed that cortactin could bind with casitas B lineage lymphoma-c (c-CBL) and counteract the function of c-CBL, a known E3 ubiquitin ligase responsible for the proteasomal degradation of mTOR. Silencing c-Cbl alleviated the impaired differentiation of osteoblasts and adipocytes caused by cortactin siRNA, while silencing mTOR mitigated the stimulation of osteoblast and adipocyte differentiation induced by cortactin overexpression. Notably, transplantation of cortactin-silenced bone marrow stromal cells (BMSCs) into the marrow of mice led to a reduction in trabecular bone mass, accompanied by a decrease in osteoblasts and an increase in osteoclasts. Furthermore, cortactin-silenced BMSCs expressed higher levels of RANKL than control BMSCs did, and promoted osteoclast differentiation when cocultured with bone marrow-derived osteoclast precursor cells. This study provides evidence that cortactin favors osteoblast differentiation by counteracting the c-CBL-induced degradation of mTOR and inhibits osteoclast differentiation by downregulating the expression of RANKL. It also suggests that maintaining an appropriate level of cortactin expression may be advantageous for maintaining bone homeostasis.
{"title":"Cortactin controls bone homeostasis through regulating the differentiation of osteoblasts and osteoclasts.","authors":"Xiaoli Yang, Meng Chen, Shuang Wang, Xingli Hu, Jie Zhou, Hairui Yuan, Endong Zhu, Baoli Wang","doi":"10.1093/stmcls/sxae031","DOIUrl":"https://doi.org/10.1093/stmcls/sxae031","url":null,"abstract":"Cortactin, a cytoskeletal protein and substrate of src kinase, is implicated in tumor aggressiveness. However, its role in bone cell differentiation remains unknown. The current study revealed that cortactin was upregulated during osteoblast and adipocyte differentiation. Functional experiments demonstrated that cortactin promoted the differentiation of mesenchymal stem/progenitor cells into osteogenic and adipogenic lineages. Mechanistically, cortactin was able to stabilize the protein level of mechanistic target of rapamycin kinase (mTOR), leading to the activation of mTOR signaling. In-depth investigation revealed that cortactin could bind with casitas B lineage lymphoma-c (c-CBL) and counteract the function of c-CBL, a known E3 ubiquitin ligase responsible for the proteasomal degradation of mTOR. Silencing c-Cbl alleviated the impaired differentiation of osteoblasts and adipocytes caused by cortactin siRNA, while silencing mTOR mitigated the stimulation of osteoblast and adipocyte differentiation induced by cortactin overexpression. Notably, transplantation of cortactin-silenced bone marrow stromal cells (BMSCs) into the marrow of mice led to a reduction in trabecular bone mass, accompanied by a decrease in osteoblasts and an increase in osteoclasts. Furthermore, cortactin-silenced BMSCs expressed higher levels of RANKL than control BMSCs did, and promoted osteoclast differentiation when cocultured with bone marrow-derived osteoclast precursor cells. This study provides evidence that cortactin favors osteoblast differentiation by counteracting the c-CBL-induced degradation of mTOR and inhibits osteoclast differentiation by downregulating the expression of RANKL. It also suggests that maintaining an appropriate level of cortactin expression may be advantageous for maintaining bone homeostasis.","PeriodicalId":231,"journal":{"name":"STEM CELLS","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140660911","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}