Stem Cell Research & Therapy最新文献

{"title":"Controlled release of hydrogel-encapsulated mesenchymal stem cells-conditioned medium promotes functional liver regeneration after hepatectomy in metabolic dysfunction-associated steatotic liver disease.","authors":"Naoya Kasahara, Takumi Teratani, Junshi Doi, Shinichiro Yokota, Kentaro Shimodaira, Yuki Kaneko, Hideyuki Ohzawa, Yasunaru Sakuma, Hideki Sasanuma, Yasuhiro Fujimoto, Taizen Urahashi, Hideyuki Yoshitomi, Hironori Yamaguchi, Joji Kitayama, Naohiro Sata","doi":"10.1186/s13287-024-03993-w","DOIUrl":"10.1186/s13287-024-03993-w","url":null,"abstract":"<p><strong>Background: </strong>Globally, prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is increasing, and there is an urgent need to develop innovative therapies that promote liver regeneration following hepatectomy for this disease. Surgical excision is a key therapeutic approach with curative potential for liver tumors. However, hepatic steatosis can lead to delayed liver regeneration and higher post-operative complication risk. Mesenchymal stem cells-conditioned medium (MSC-CM) is considered a rich source of paracrine factors that can repair tissues and restore function of damaged organs. Meanwhile, hydrogels have been widely recognized to load MSC secretome and achieve sustained release. This study aimed to evaluate the therapeutic effect of hydrogel-encapsulated MSC-CM on liver regeneration following partial hepatectomy (PHx) in a rodent model of diet-induced hepatic steatosis.</p><p><strong>Methods: </strong>Male Lewis rats were fed with a methionine and choline-deficient diet. After 3 weeks of feeding, PHx was performed and rats were randomly allocated into two groups that received hydrogel-encapsulated MSC-CM or vehicle via the intra-mesenteric space of the superior mesenteric vein (SMV).</p><p><strong>Results: </strong>The regeneration of the remnant liver at 30 and 168 h after PHx was significantly accelerated, and the expressions of proliferating cell nuclear antigen were significantly enhanced in the MSC-CM group. MSC-CM treatment significantly increased hepatic ATP and β-hydroxybutyrate content at 168 h after PHx, indicating that MSC-CM fosters regeneration not only in volume but also in functionality. The number of each TUNEL- and cleaved caspase-3 positive nuclei in hepatocytes at 9 h after PHx were significantly decreased in the MSC-CM group, suggesting that MSC-CM suppressed apoptosis. MSC-CM increased serum immunoregulatory cytokine interleukin-10 and interleukin-13 at 30 h after PHx. Additionally, mitotic figures and cyclin D1 expression decreased and hepatocyte size increased in the MSC-CM group, implying that this mode of regeneration was mainly through cell hypertrophy rather than cell division.</p><p><strong>Conclusions: </strong>MSC-CM represents a novel therapeutic approach for patients with MASLD requiring PHx.</p>","PeriodicalId":21876,"journal":{"name":"Stem Cell Research & Therapy","volume":"15 1","pages":"395"},"PeriodicalIF":7.1,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11536549/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142576939","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}

{"title":"Cisplatin-encapsulated TRAIL-engineered exosomes from human chorion-derived MSCs for targeted cervical cancer therapy.","authors":"Miaomiao Ye, Tingxian Liu, Liqing Miao, Huihui Ji, Zhihui Xu, Huihui Wang, Jian'an Zhang, Xueqiong Zhu","doi":"10.1186/s13287-024-04006-6","DOIUrl":"10.1186/s13287-024-04006-6","url":null,"abstract":"<p><strong>Background: </strong>Cisplatin (DDP) is an efficacious and widely applied chemotherapeutic drug for cervical cancer patients who are diagnosed as metastatic and inoperable, or desiring fertility preservation. Tumor necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL) selectively triggers cancer cells apoptosis by binding to cognate death receptors (DR4 and DR5). Mesenchymal stem cells-derived exosomes (MSCs-Exo) have been regarded as ideal drug carriers on account of their nanoscale, low toxicity, low immunogenicity, high stability, biodegradability, and abundant sources.</p><p><strong>Methods: </strong>Human chorion-derived mesenchymal stem cells (hCD-MSCs) were isolated by adherent culture method. TRAIL-engineered hCD-MSCs (hCD-MSCs^TRAIL) were constructed by lentivirus transfection, and its secreted Exo (hCD-MSCs-Exo^TRAIL) were acquired by differential centrifugation and confirmed to overexpress TRAIL by western blotting. Next, nanoscale drug delivery systems (DDP & hCD-MSCs-Exo^TRAIL) were fabricated by loading DDP into hCD-MSCs-Exo^TRAIL via electroporation. The CCK-8 assay and flow cytometry were conducted to explore the proliferation and apoptosis of cervical cancer cells (SiHa and HeLa), respectively. Cervical cancer-bearing nude mice were constructed to examine the antitumor activity and biosafety of DDP & hCD-MSCs-Exo^TRAIL in vivo.</p><p><strong>Results: </strong>Compared with hCD-MSCs-Exo, hCD-MSCs-Exo^TRAIL weakened proliferation and enhanced apoptosis of cervical cancer cells. DDP & hCD-MSCs-Exo^TRAIL were proved to retard cervical cancer cell proliferation and propel cell apoptosis more effectively than DDP or hCD-MSCs-Exo^TRAIL alone in vitro. In cervical cancer-bearing mice, DDP & hCD-MSCs-Exo^TRAIL evidently hampered tumor growth, and its role in inducing apoptosis was mechanistically associated with JNK/p-c-Jun activation and survivin suppression. Moreover, DDP & hCD-MSCs-Exo^TRAIL showed favorable biosafety in vivo.</p><p><strong>Conclusions: </strong>DDP & hCD-MSCs-Exo^TRAIL nanoparticles exhibited great promise for cervical cancer treatment as an Exo-based chemo-gene combinational therapy in clinical practice.</p>","PeriodicalId":21876,"journal":{"name":"Stem Cell Research & Therapy","volume":"15 1","pages":"396"},"PeriodicalIF":7.1,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11536590/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142576938","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}

{"title":"The role of mitochondrial transfer in the suppression of CD8⁺ T cell responses by Mesenchymal stem cells.","authors":"Loic Vaillant, Waseem Akhter, Jean Nakhle, Matthieu Simon, Martin Villalba, Christian Jorgensen, Marie-Luce Vignais, Javier Hernandez","doi":"10.1186/s13287-024-03980-1","DOIUrl":"10.1186/s13287-024-03980-1","url":null,"abstract":"<p><strong>Background: </strong>. CD8⁺ Cytotoxic T lymphocytes play a key role in the pathogenesis of autoimmune diseases and clinical conditions such as graft versus host disease and graft rejection. Mesenchymal Stromal Cells (MSCs) are multipotent cells with tissue repair and immunomodulatory capabilities. Since they are able to suppress multiple pathogenic immune responses, MSCs have been proposed as a cellular therapy for the treatment of immune-mediated diseases. However, the mechanisms underlying their immunosuppressive properties are not yet fully understood. MSCs have the remarkable ability to sense tissue injury and inflammation and respond by donating their own mitochondria to neighboring cells. Whether mitochondrial transfer has any role in the repression of CD8⁺ responses is unknown.</p><p><strong>Methods and results: </strong>. We have utilized CD8⁺ T cells from Clone 4 TCR transgenic mice that differentiate into effector cells upon activation in vitro and in vivo to address this question. Allogeneic bone marrow derived MSCs, co-cultured with activated Clone 4 CD8⁺ T cells, decreased their expansion, the production of the effector cytokine IFNγ and their diabetogenic potential in vivo. Notably, we found that during this interaction leading to suppression, MSCs transferred mitochondria to CD8⁺ T cells as evidenced by FACS and confocal microscopy. Transfer of MSC mitochondria to Clone 4 CD8⁺ T cells also resulted in decreased expansion and production of IFNγ upon activation. These effects overlapped and were additive with those of prostaglandin E2 secreted by MSCs. Furthermore, preventing mitochondrial transfer in co-cultures diminished the ability of MSCs to inhibit IFNγ production. Finally, we demonstrated that both MSCs and MSC mitochondria downregulated T-bet and Eomes expression, key transcription factors for CTL differentiation, on activated CD8⁺ T cells.</p><p><strong>Conclusion: </strong>. In this report we showed that MSCs are able to interact with CD8⁺ T cells and transfer them their mitochondria. Mitochondrial transfer contributed to the global suppressive effect of MSCs on CD8⁺ T cell activation by downregulating T-bet and Eomes expression resulting in impaired IFNγ production of activated CD8⁺ T cells.</p>","PeriodicalId":21876,"journal":{"name":"Stem Cell Research & Therapy","volume":"15 1","pages":"394"},"PeriodicalIF":7.1,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11536934/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142576940","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}

{"title":"Advances in the roles and mechanisms of mesenchymal stem cell derived microRNAs on periodontal tissue regeneration.","authors":"Jiaxiang Zhang, Liangrui Chen, Jialu Yu, Weidong Tian, Shujuan Guo","doi":"10.1186/s13287-024-03998-5","DOIUrl":"10.1186/s13287-024-03998-5","url":null,"abstract":"<p><p>Periodontitis is one of the most prevalent oral diseases leading to tooth loss in adults, and is characterized by the destruction of periodontal supporting structures. Traditional therapies for periodontitis cannot achieve ideal regeneration of the periodontal tissue. Mesenchymal stem cells (MSCs) represent a promising approach to periodontal tissue regeneration. Recently, the prominent role of MSCs in this context has been attributed to microRNAs (miRNAs), which participate in post-transcriptional regulation and are crucial for various physiological and pathological processes. Additionally, they function as indispensable elements in extracellular vesicles, which protect them from degradation. In periodontitis, MSCs-derived miRNAs play a pivotal role in cellular proliferation and differentiation, angiogenesis of periodontal tissues, regulating autophagy, providing anti-apoptotic effects, and mediating the inflammatory microenvironment. As a cell-free strategy, their small size and ability to target related sets of genes and regulate signaling networks predispose miRNAs to become ideal candidates for periodontal tissue regeneration. This review aims to introduce and summarize the potential functions and mechanisms of MSCs-derived miRNAs in periodontal tissue repair and regeneration.</p>","PeriodicalId":21876,"journal":{"name":"Stem Cell Research & Therapy","volume":"15 1","pages":"393"},"PeriodicalIF":7.1,"publicationDate":"2024-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11533400/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142569397","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}

{"title":"Mesenchymal stromal cells alleviate APAP-induced liver injury via extracellular vesicle-mediated regulation of the miR-186-5p/CXCL1 axis.","authors":"Erming Zhao, Rukang Liang, Panlong Li, Di Lu, Shuhan Chen, Weikeng Tan, Yunfei Qin, Yana Zhang, Yingcai Zhang, Qi Zhang, Qiuli Liu","doi":"10.1186/s13287-024-03995-8","DOIUrl":"10.1186/s13287-024-03995-8","url":null,"abstract":"<p><strong>Background: </strong>Acetaminophen (APAP) overdose is a significant cause of drug-induced liver injury (DILI). N-acetylcysteine (NAC) is the first-line agent used in the clinic. However, it rarely benefits patients with advanced APAP toxicity. Mesenchymal stromal cells (MSCs) have demonstrated potential in treating DILI. However, the specific mechanism by which MSCs protect against APAP-induced liver injury remains unclear.</p><p><strong>Methods: </strong>APAP was injected intraperitoneally to induce a liver injury model. We then detected histopathology, biochemical indices, and inflammatory cytokine levels to assess the efficacy of MSCs and MSC extracellular vesicles (MSC-EVs). Flow cytometry was performed to reveal the immunoregulatory effects of MSCs and MSC-EVs on the neutrophils. RNA sequencing (RNA-Seq) of liver tissues was used to identify critical target genes for MSC treatment.</p><p><strong>Results: </strong>MSC and MSC-EV treatment effectively alleviated APAP-induced liver injury and inhibited neutrophil infiltration. RNA-Seq analysis and ELISA data indicated that C-X-C motif chemokine 1 (CXCL1), a chemoattractant for neutrophils, was a key molecule in the MSC-mediated amelioration of APAP-induced liver damage. In addition, neutralization of CXCL1 reduced APAP-induced liver damage, which was accompanied by decreased neutrophil infiltration. Importantly, we verified that MSC-EV-derived miR-186-5p directly binds to the 3'-UTR of Cxcl1 to inhibit its expression in hepatocytes. The agomir miR-186-5p showed excellent potential for the treatment of DILI.</p><p><strong>Conclusions: </strong>Our findings suggest that MSCs and MSC-EVs are an effective approach to mitigate DILI. Targeting the miR-186-5p/CXCL1 axis is a promising approach to improve the efficacy of MSCs and MSC-EVs in the treatment of DILI.</p>","PeriodicalId":21876,"journal":{"name":"Stem Cell Research & Therapy","volume":"15 1","pages":"392"},"PeriodicalIF":7.1,"publicationDate":"2024-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11533353/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142569398","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}

{"title":"Advances in regulating endothelial-mesenchymal transformation through exosomes.","authors":"Sun Sishuai, Gu Lingui, Li Pengtao, Bao Xinjie, Wei Junji","doi":"10.1186/s13287-024-04010-w","DOIUrl":"10.1186/s13287-024-04010-w","url":null,"abstract":"<p><p>Endothelial-mesenchymal transformation (EndoMT) is the process through which endothelial cells transform into mesenchymal cells, affecting their morphology, gene expression, and function. EndoMT is a potential risk factor for cardiovascular and cerebrovascular diseases, tumor metastasis, and fibrosis. Recent research has highlighted the role of exosomes, a mode of cellular communication, in the regulation of EndoMT. Exosomes from diseased tissues and microenvironments can promote EndoMT, increase endothelial permeability, and compromise the vascular barrier. Conversely, exosomes derived from stem cells or progenitor cells can inhibit the EndoMT process and preserve endothelial function. By modifying exosome membranes or contents, we can harness the advantages of exosomes as carriers, enhancing their targeting and ability to inhibit EndoMT. This review aims to systematically summarize the regulation of EndoMT by exosomes in different disease contexts and provide effective strategies for exosome-based EndoMT intervention.</p>","PeriodicalId":21876,"journal":{"name":"Stem Cell Research & Therapy","volume":"15 1","pages":"391"},"PeriodicalIF":7.1,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11529026/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142558821","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}

{"title":"Dental stem cell dynamics in periodontal ligament regeneration: from mechanism to application.","authors":"Shuyi Wen, Xiao Zheng, Wuwei Yin, Yushan Liu, Ruijie Wang, Yaqi Zhao, Ziyi Liu, Cong Li, Jincheng Zeng, Mingdeng Rong","doi":"10.1186/s13287-024-04003-9","DOIUrl":"10.1186/s13287-024-04003-9","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Periodontitis, a globally prevalent chronic inflammatory disease is characterized by the progressive degradation of tooth-supporting structures, particularly the periodontal ligament (PDL), which can eventually result in tooth loss. Despite the various clinical interventions available, most focus on symptomatic relief and lack substantial evidence of supporting the functional regeneration of the PDL. Dental stem cells (DSCs), with their homology and mesenchymal stem cell (MSC) properties, have gained significant attention as a potential avenue for PDL regeneration. Consequently, multiple therapeutic strategies have been developed to enhance the efficacy of DSC-based treatments and improve clinical outcomes. This review examines the mechanisms by which DSCs and their derivatives promote PDL regeneration, and explores the diverse applications of exogenous implantation and endogenous regenerative technology (ERT) aimed at amplifying the regenerative capacity of endogenous DSCs. Additionally, the persistent challenges and controversies surrounding DSC therapies are discussed, alongside an evaluation of the limitations in current research on the underlying mechanisms and innovative applications of DSCs in PDL regeneration with the aim of providing new insights for future development. Periodontitis, a chronic inflammatory disease, represents a major global public health concern, affecting a significant proportion of the population and standing as the leading cause tooth loss in adults. The functional periodontal ligament (PDL) plays an indispensable role in maintaining periodontal health, as its structural and biological integrity is crucial for the long-term prognosis of periodontal tissues. It is widely recognized as the cornerstone of periodontal regeneration Despite the availability of various treatments, ranging from nonsurgical interventions to guided tissue regeneration (GTR) techniques, these methods have shown limited success in achieving meaningful PDL regeneration. As a result, the inability to fully restore PDL function underscores the urgent need for innovative therapeutic strategies at reconstructing this essential structure. Stem cell therapy, known for its regenerative and immunomodulatory potential, offers a promising approach for periodontal tissue repair. Their application marks a significant paradigm shift in the treatment of periodontal diseases, opening new avenues for functional PDL regeneration. However, much of the current research has primarily focused on the regeneration of alveolar bone and gingiva, as these hard and soft tissues can be more easily evaluated through visual assessment. The complexity of PDL structure, coupled with the intricate interactions among cellular and molecular components, presents significant scientific and clinical hurdles in translating DSC research into practical therapeutic applications. This review provides a thorough exploration of DSC dynamics in periodontal regeneration, detailing their","PeriodicalId":21876,"journal":{"name":"Stem Cell Research & Therapy","volume":"15 1","pages":"389"},"PeriodicalIF":7.1,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11526537/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142558823","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}

{"title":"Advances in retinal pigment epithelial cell transplantation for retinal degenerative diseases.","authors":"Hang Liu, Suber S Huang, Gopal Lingam, Dan Kai, Xinyi Su, Zengping Liu","doi":"10.1186/s13287-024-04007-5","DOIUrl":"10.1186/s13287-024-04007-5","url":null,"abstract":"<p><p>Retinal degenerative diseases are a leading cause of vision loss and blindness globally, impacting millions. These diseases result from progressive damage to retinal pigment epithelial (RPE) cells for which no curative or palliative treatments exist. Cell therapy, particularly RPE transplantation, has emerged as a promising strategy for vision restoration. This review provides a comprehensive overview of the recent advancements in clinical trials related to RPE transplantation. We discuss scaffold-free and scaffold-based approaches, including RPE cell suspensions and pre-organized RPE monolayers on biomaterial scaffolds. Key considerations, such as the form and preparation of RPE implants, delivery devices, strategies, and biodegradability of scaffolds, are examined. The article also explores the challenges and opportunities in RPE scaffold development, emphasising the crucial need for functional integration, immunomodulation, and long-term biocompatibility to ensure therapeutic efficacy. We also highlight ongoing efforts to optimise RPE transplantation methods and their potential to address retinal degenerative diseases.</p>","PeriodicalId":21876,"journal":{"name":"Stem Cell Research & Therapy","volume":"15 1","pages":"390"},"PeriodicalIF":7.1,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11526680/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142558822","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}

{"title":"Identification of CD141⁺vasculogenic precursor cells from human bone marrow and their endothelial engagement in the arteriogenesis by co-transplantation with mesenchymal stem cells.","authors":"Gabee Park, Dae Yeon Hwang, Do Young Kim, Ji Young Han, Euiseon Lee, Hwakyung Hwang, Jeong Seop Park, Dae Wook Kim, Seonmin Hong, Sung Vin Yim, Hyun Sook Hong, Youngsook Son","doi":"10.1186/s13287-024-03994-9","DOIUrl":"10.1186/s13287-024-03994-9","url":null,"abstract":"<p><strong>Background: </strong>Critical limb ischemia (CLI) is a condition characterized by insufficient blood flow to the lower limbs, resulting in severe ischemia and potentially leading to amputation. This study aims to identify novel vasculogenic precursor cells (VPCs) in human bone marrow and evaluate their efficacy in combination with bone marrow-derived mesenchymal stem cells (BM-MSCs) for the treatment of CLI.</p><p><strong>Methods: </strong>Ex vivo cultured VPCs and BM-MSCs from bone marrow were characterized and their effects on neovascularization and long-term tissue regeneration were tested in a mouse CLI model.</p><p><strong>Results: </strong>VPCs, expressing high levels of hepatocyte growth factor and c-MET, were identified from human bone marrow aspirates. These cells exhibited strong vasculogenic capacity in vitro but possessed a cellular phenotype distinct from those of previously reported endothelial precursor cells in circulation or cord blood. They also expressed most surface markers of BM-MSCs and demonstrated multipotent differentiation ability. Screening of 376 surface markers revealed that VPCs uniquely display CD141 (thrombomodulin). CD141⁺VPCs are present in BM aspirates as a rare population and can be expanded ex vivo with a population doubling time of approximately 20 h, generating an elaborate vascular network even under angiogenic factor-deficient conditions and recruiting BM-MSCs to the network as pericyte-like cells. Intramuscular transplantation of a combination of human CD141⁺VPCs and BM-MSCs at a ratio of 2:1 resulted in limb salvage, blood flow recovery, and regeneration of large vessels in the femoral artery-removed CLI model, with an efficacy superior to that of singular transplantation. Importantly, large arteries and arterioles in dual cell transplantation expressed human CD31 in the intima and human α-smooth muscle actin in media layer at 4 and 12 weeks, likely indicating their lineage commitment to endothelial cells and vascular smooth muscle, respectively, in vivo.</p><p><strong>Conclusion: </strong>Dual-cell therapy using BM-derived CD141⁺ VPCs and BM-MSCs holds potential for further development in clinical trials to treat peripheral artery disease and diabetic ulcers.</p>","PeriodicalId":21876,"journal":{"name":"Stem Cell Research & Therapy","volume":"15 1","pages":"388"},"PeriodicalIF":7.1,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11526567/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142558824","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}

{"title":"Targeted hematopoietic stem cell depletion through SCF-blockade.","authors":"Yan Yi Chan, Pui Yan Ho, Carla Dib, Leah Swartzrock, Maire Rayburn, Hana Willner, Ethan Ko, Katie Ho, Julian D Down, Adam C Wilkinson, Hiro Nakauchi, Morgane Denis, Taylor Cool, Agnieszka Czechowicz","doi":"10.1186/s13287-024-03981-0","DOIUrl":"10.1186/s13287-024-03981-0","url":null,"abstract":"<p><strong>Background: </strong>Hematopoietic stem cell transplantation (HSCT) is a curative treatment for many diverse blood and immune diseases. However, HSCT regimens currently commonly utilize genotoxic chemotherapy and/or total body irradiation (TBI) conditioning which causes significant morbidity and mortality through inducing broad tissue damage triggering infections, graft vs. host disease, infertility, and secondary cancers. We previously demonstrated that targeted monoclonal antibody (mAb)-based HSC depletion with anti(α)-CD117 mAbs could be an effective alternative conditioning approach for HSCT without toxicity in severe combined immunodeficiency (SCID) mouse models, which has prompted parallel clinical αCD117 mAbs to be developed and tested as conditioning agents in clinical trials starting with treatment of patients with SCID. Subsequent efforts have built upon this work to develop various combination approaches, though none are optimal and how any of these mAbs fully function is unknown.</p><p><strong>Methods: </strong>To improve efficacy of mAb-based conditioning as a stand-alone conditioning approach for all HSCT settings, it is critical to understand the mechanistic action of αCD117 mAbs on HSCs. Here, we compare the antagonistic properties of αCD117 mAb clones including ACK2, 2B8, and 3C11 as well as ACK2 fragments in vitro and in vivo in both SCID and wildtype (WT) mouse models. Further, to augment efficacy, combination regimens were also explored.</p><p><strong>Results: </strong>We confirm that only ACK2 inhibits SCF binding fully and prevents HSC proliferation in vitro. Further, we verify that this corresponds to HSC depletion in vivo and donor engraftment post HSCT in SCID mice. We also show that SCF-blocking αCD117 mAb fragment derivatives retain similar HSC depletion capacity with enhanced engraftment post HSCT in SCID settings, but only full αCD117 mAb ACK2 in combination with αCD47 mAb enables enhanced donor HSC engraftment in WT settings, highlighting that the Fc region is not required for single-agent efficacy in SCID settings but is required in immunocompetent settings. This combination was the only non-genotoxic conditioning approach that enabled robust donor engraftment post HSCT in WT mice.</p><p><strong>Conclusion: </strong>These findings shed new insights into the mechanism of αCD117 mAb-mediated HSC depletion. Further, they highlight multiple approaches for efficacy in SCID settings and optimal combinations for WT settings. This work is likely to aid in the development of clinical non-genotoxic HSCT conditioning approaches that could benefit millions of people world-wide.</p>","PeriodicalId":21876,"journal":{"name":"Stem Cell Research & Therapy","volume":"15 1","pages":"387"},"PeriodicalIF":7.1,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11523590/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142547546","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}