Pub Date : 2025-01-01Epub Date: 2025-10-15DOI: 10.1177/09636897251378231
Itay Lotan, Benjamin R Johnston, Shuhei Nishiyama, Jin Myoung Seok, Amy Wright, Stanley Bazarek, Michael Levy
Cell-based therapies, particularly transplanted human oligodendrocyte progenitor cells (OPCs), are being explored for neuroprotection and remyelination in demyelinating diseases of the central nervous system (CNS). In this study, we investigated the potential of OPC transplantation into the optic nerve of dark agouti (DA) rats with experimental autoimmune encephalomyelitis (EAE). Human OPCs were transplanted 30 days after EAE induction in one optic nerve, while the contralateral nerve was injected with a vehicle. FTY720 (fingolimod) was administered starting from day 25 post-EAE to prevent graft rejection. Rats were monitored clinically and electrophysiologically using visually evoked potentials (VEPs) for up to 90 days post-transplant. Histological analysis of OPC viability, myelin, and axonal integrity was performed on days 30, 60, and 90 post-transplant. At days 30 and 60, sparse OPCs were detected in the injected optic nerve. However, no live cells were detected on day 90. There were no significant differences in myelin or axonal integrity between the OPC- and vehicle-injected nerves. The VEP traces were severely distorted throughout the 90-day follow-up. This approach did not show long-term viability following direct injection of OPCs in the optic nerve of EAE rats. Challenges related to graft rejection and cell transplantation are discussed, with implications for future research in cell-based therapies.
{"title":"Applicability of regenerative oligodendrocyte precursor cell optic nerve transplantation in rat model of demyelinating disease.","authors":"Itay Lotan, Benjamin R Johnston, Shuhei Nishiyama, Jin Myoung Seok, Amy Wright, Stanley Bazarek, Michael Levy","doi":"10.1177/09636897251378231","DOIUrl":"10.1177/09636897251378231","url":null,"abstract":"<p><p>Cell-based therapies, particularly transplanted human oligodendrocyte progenitor cells (OPCs), are being explored for neuroprotection and remyelination in demyelinating diseases of the central nervous system (CNS). In this study, we investigated the potential of OPC transplantation into the optic nerve of dark agouti (DA) rats with experimental autoimmune encephalomyelitis (EAE). Human OPCs were transplanted 30 days after EAE induction in one optic nerve, while the contralateral nerve was injected with a vehicle. FTY720 (fingolimod) was administered starting from day 25 post-EAE to prevent graft rejection. Rats were monitored clinically and electrophysiologically using visually evoked potentials (VEPs) for up to 90 days post-transplant. Histological analysis of OPC viability, myelin, and axonal integrity was performed on days 30, 60, and 90 post-transplant. At days 30 and 60, sparse OPCs were detected in the injected optic nerve. However, no live cells were detected on day 90. There were no significant differences in myelin or axonal integrity between the OPC- and vehicle-injected nerves. The VEP traces were severely distorted throughout the 90-day follow-up. This approach did not show long-term viability following direct injection of OPCs in the optic nerve of EAE rats. Challenges related to graft rejection and cell transplantation are discussed, with implications for future research in cell-based therapies.</p>","PeriodicalId":9721,"journal":{"name":"Cell Transplantation","volume":"34 ","pages":"9636897251378231"},"PeriodicalIF":3.2,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12536187/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145291107","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01Epub Date: 2025-10-18DOI: 10.1177/09636897251376125
Julong Hu, Wenxu Peng, Yeltai Nurzat, Qi Zhang, Zaihuan Lin, Jianlei Xie, Meiqian Xu, Hang Ji, Gang Liang, Zhihua Zhang, Wenjing Liao, Xiaowen Zhang
Allogeneic skin transplantation faces significant immunological challenges due to immune rejection, primarily mediated by dendritic cells (DCs). Adipose-derived stem cells (ADSCs) possess immunomodulatory effects; however, the underlying molecular mechanisms in regulating DC function remain unclear. This study aimed to investigate the regulatory effects of ADSCs and tumor necrosis factor-α-stimulated gene 6 (TSG-6) secreted by ADSCs on DC in the murine allogeneic skin transplantation. Following transplantation, recipients received ADSCs, TSG-6 knockdown ADSCs (ADSCs-shTSG-6), or control treatments. Immune cell infiltration and cytokine expression were analyzed by flow cytometry and immunohistochemistry. Transwell assays were used to assess the effect of TSG-6 on DCs migration. TSG-6-related gene expression profiles were explored using transcriptomic analysis and validated by RT-qPCR. ADSC treatment significantly reduced the migration of DCs to the recipient than the ADSCs-shTSG-6 treatment, while reducing the levels of macrophages, lymphocytes, and pro-inflammatory cytokines. ADSC-derived TSG-6 inhibited DCs migration, an effect diminished upon TSG-6 knockdown and restored by TSG-6 supplementation. Transcriptomic analysis identified a panel of immune-related genes (ADM, GHRH, SELENBP1, NDRG1) regulated by TSG-6. These findings indicate that ADSCs enhance graft tolerance by inhibiting DCs migration via TSG-6 secretion, highlighting TSG-6 as a promising therapeutic target for preventing transplant rejection.
{"title":"Adipose-derived stem cells inhibit dendritic cell migration by secreting tumor necrosis factor-α-stimulated gene 6 to improve the allogeneic skin transplantation survival rate in mice.","authors":"Julong Hu, Wenxu Peng, Yeltai Nurzat, Qi Zhang, Zaihuan Lin, Jianlei Xie, Meiqian Xu, Hang Ji, Gang Liang, Zhihua Zhang, Wenjing Liao, Xiaowen Zhang","doi":"10.1177/09636897251376125","DOIUrl":"10.1177/09636897251376125","url":null,"abstract":"<p><p>Allogeneic skin transplantation faces significant immunological challenges due to immune rejection, primarily mediated by dendritic cells (DCs). Adipose-derived stem cells (ADSCs) possess immunomodulatory effects; however, the underlying molecular mechanisms in regulating DC function remain unclear. This study aimed to investigate the regulatory effects of ADSCs and tumor necrosis factor-α-stimulated gene 6 (TSG-6) secreted by ADSCs on DC in the murine allogeneic skin transplantation. Following transplantation, recipients received ADSCs, TSG-6 knockdown ADSCs (ADSCs-shTSG-6), or control treatments. Immune cell infiltration and cytokine expression were analyzed by flow cytometry and immunohistochemistry. Transwell assays were used to assess the effect of TSG-6 on DCs migration. TSG-6-related gene expression profiles were explored using transcriptomic analysis and validated by RT-qPCR. ADSC treatment significantly reduced the migration of DCs to the recipient than the ADSCs-shTSG-6 treatment, while reducing the levels of macrophages, lymphocytes, and pro-inflammatory cytokines. ADSC-derived TSG-6 inhibited DCs migration, an effect diminished upon TSG-6 knockdown and restored by TSG-6 supplementation. Transcriptomic analysis identified a panel of immune-related genes (ADM, GHRH, SELENBP1, NDRG1) regulated by TSG-6. These findings indicate that ADSCs enhance graft tolerance by inhibiting DCs migration via TSG-6 secretion, highlighting TSG-6 as a promising therapeutic target for preventing transplant rejection.</p>","PeriodicalId":9721,"journal":{"name":"Cell Transplantation","volume":"34 ","pages":"9636897251376125"},"PeriodicalIF":3.2,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12547123/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145312562","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Glucose-stimulated insulin secretion (GSIS) testing of isolated islets of Langerhans is crucial for assessing β-cell function, yet protocol variability complicates result interpretation. This study investigated insulin secretion heterogeneity across 576 donors and examined the influence of donor characteristics on secretory responses. We compared static incubation (n = 408) and dynamic perifusion (n = 168) techniques using standardized glucose stimulation protocols (3 vs 15 mM). While both methods showed comparable stimulation indices (r2 = 0.652), dynamic perifusion uniquely captured temporal secretion patterns and revealed greater dynamic range in insulin responses. Notably, dynamic perifusion, with insulin content normalization, revealed a 22-fold variation in stimulation index across donors. Body mass index (BMI) and HbA1c significantly influenced basal insulin secretion, particularly in donors with glucose intolerance and type 2 diabetes (T2D) (HbA1c ≥ 6.5%). Cluster analysis identified two distinct groups based on age, BMI/body surface area (BSA), and HbA1c, which strongly predicted insulin secretion patterns, whereas donor sex had no measurable impact. This large-scale study demonstrates the superiority of standardized perifusion over static incubation for resolving islet glucose responses. By capturing dynamic secretion profiles, perifusion reveals substantial donor heterogeneity, primarily driven by BMI and HbA1c through their effects on basal insulin secretion.
葡萄糖刺激胰岛素分泌(GSIS)测试孤立的朗格汉斯胰岛是评估β细胞功能的关键,但方案的可变性使结果的解释复杂化。本研究调查了576名供体胰岛素分泌的异质性,并检查了供体特征对分泌反应的影响。我们比较了采用标准化葡萄糖刺激方案(3 vs 15 mM)的静态孵育(n = 408)和动态灌注(n = 168)技术。虽然两种方法的刺激指数相当(r2 = 0.652),但动态灌注独特地捕获了时间分泌模式,并揭示了胰岛素反应的更大动态范围。值得注意的是,在胰岛素含量正常化的情况下,动态灌注显示,不同供体的刺激指数变化了22倍。体重指数(BMI)和糖化血红蛋白(HbA1c)显著影响基础胰岛素分泌,尤其是糖耐受不良和2型糖尿病(T2D)患者(糖化血红蛋白≥6.5%)。聚类分析根据年龄、BMI/体表面积(BSA)和HbA1c确定了两组不同的胰岛素分泌模式,而供体性别没有可测量的影响。这项大规模的研究表明,在解决胰岛葡萄糖反应方面,标准化灌注优于静态孵育。通过捕获动态分泌谱,灌注揭示了大量供体的异质性,主要由BMI和HbA1c通过对基础胰岛素分泌的影响驱动。
{"title":"Standardized dynamic glucose testing reveals donor-dependent heterogeneity in human islet function.","authors":"Priyadarshini Gnanasekar, Chiara Saponaro, Markus Mühlemann, Chimene Amayene Amassogo, Anais Coddeville, Julien Thevenet, Nathalie Delalleau, Pauline Petit, Arnaud Hanssen, Gianni Pasquetti, Valentin Lericque, Mikael Chetboun, Violeta Raverdy, Isabel Gonzalez-Mariscal, Marie-Christine Vantyghem, Caroline Bonner, François Pattou, Julie Kerr-Conte, Valery Gmyr","doi":"10.1177/09636897251350654","DOIUrl":"10.1177/09636897251350654","url":null,"abstract":"<p><p>Glucose-stimulated insulin secretion (GSIS) testing of isolated islets of Langerhans is crucial for assessing β-cell function, yet protocol variability complicates result interpretation. This study investigated insulin secretion heterogeneity across 576 donors and examined the influence of donor characteristics on secretory responses. We compared static incubation (<i>n =</i> 408) and dynamic perifusion (<i>n =</i> 168) techniques using standardized glucose stimulation protocols (3 vs 15 mM). While both methods showed comparable stimulation indices (<i>r</i><sup>2</sup> = 0.652), dynamic perifusion uniquely captured temporal secretion patterns and revealed greater dynamic range in insulin responses. Notably, dynamic perifusion, with insulin content normalization, revealed a 22-fold variation in stimulation index across donors. Body mass index (BMI) and HbA1c significantly influenced basal insulin secretion, particularly in donors with glucose intolerance and type 2 diabetes (T2D) (HbA1c ≥ 6.5%). Cluster analysis identified two distinct groups based on age, BMI/body surface area (BSA), and HbA1c, which strongly predicted insulin secretion patterns, whereas donor sex had no measurable impact. This large-scale study demonstrates the superiority of standardized perifusion over static incubation for resolving islet glucose responses. By capturing dynamic secretion profiles, perifusion reveals substantial donor heterogeneity, primarily driven by BMI and HbA1c through their effects on basal insulin secretion.</p>","PeriodicalId":9721,"journal":{"name":"Cell Transplantation","volume":"34 ","pages":"9636897251350654"},"PeriodicalIF":3.2,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12535635/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145539408","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01Epub Date: 2025-10-31DOI: 10.1177/09636897251371114
Megan Tennant, Melissa Cunningham, Richard ONeil
Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder characterized by widespread immune dysregulation and systemic inflammation. Among its many manifestations, lupus nephritis (LN) stands out as one of the most severe and life-threatening complications, affecting up to 60% of SLE patients. LN primarily results from a type III hypersensitivity reaction in which immune complexes are deposited within the kidney. This leads to progressive glomerular and tubulointerstitial lesions compromising renal function. A significant portion of patients presenting with LN will progress to end-stage renal disease (ERSD). Despite advances in treatment strategies, including standard and targeted biologic immunosuppressants, many patients with LN fail to achieve long-term remission, leaving a significant need for safer and more effective therapies. In recent years, T-cell-based therapies have emerged as a promising frontier in the treatment of a variety of conditions including autoimmune diseases. Specifically, chimeric antigen receptor (CAR) T-cell therapies aimed at depleting antibody-producing B cells have demonstrated the ability to restore immune tolerance in several preclinical models of diseases with B-cell-driven pathologies, including SLE. In the case of LN, CAR T-cell therapies have also been deployed in clinical trials to treat patients with refractory disease. The positive results of initial clinical trials provide strong evidence that B-cell-targeted cellular therapies such as CAR T cells targeting B-cell markers CD19 and B-cell maturation antigen (BCMA) might be an effective modality for rebalancing the immune system through the elimination of autoreactive B cells. This review examines the current state of CAR T-cell therapies and their applications in LN by exploring the mechanisms, challenges, and the potential of this unique treatment approach.
{"title":"Harnessing T-cell therapy for lupus nephritis: Opportunities and challenges.","authors":"Megan Tennant, Melissa Cunningham, Richard ONeil","doi":"10.1177/09636897251371114","DOIUrl":"10.1177/09636897251371114","url":null,"abstract":"<p><p>Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder characterized by widespread immune dysregulation and systemic inflammation. Among its many manifestations, lupus nephritis (LN) stands out as one of the most severe and life-threatening complications, affecting up to 60% of SLE patients. LN primarily results from a type III hypersensitivity reaction in which immune complexes are deposited within the kidney. This leads to progressive glomerular and tubulointerstitial lesions compromising renal function. A significant portion of patients presenting with LN will progress to end-stage renal disease (ERSD). Despite advances in treatment strategies, including standard and targeted biologic immunosuppressants, many patients with LN fail to achieve long-term remission, leaving a significant need for safer and more effective therapies. In recent years, T-cell-based therapies have emerged as a promising frontier in the treatment of a variety of conditions including autoimmune diseases. Specifically, chimeric antigen receptor (CAR) T-cell therapies aimed at depleting antibody-producing B cells have demonstrated the ability to restore immune tolerance in several preclinical models of diseases with B-cell-driven pathologies, including SLE. In the case of LN, CAR T-cell therapies have also been deployed in clinical trials to treat patients with refractory disease. The positive results of initial clinical trials provide strong evidence that B-cell-targeted cellular therapies such as CAR T cells targeting B-cell markers CD19 and B-cell maturation antigen (BCMA) might be an effective modality for rebalancing the immune system through the elimination of autoreactive B cells. This review examines the current state of CAR T-cell therapies and their applications in LN by exploring the mechanisms, challenges, and the potential of this unique treatment approach.</p>","PeriodicalId":9721,"journal":{"name":"Cell Transplantation","volume":"34 ","pages":"9636897251371114"},"PeriodicalIF":3.2,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12579727/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145408171","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01Epub Date: 2025-10-31DOI: 10.1177/09636897251383464
Xiao-Ning Wang, Yu-Qi Wang, Rui-Min Liu, Juan Ren, Hua-Chao Zhu, Peng-Cheng He
This study compared the efficacy and safety of the modified BEAM (mitoxantrone hydrochloride liposome replacing melphalan) versus BEAM/BEAC as a conditioning regimen for autologous hematopoietic stem cell transplantation (auto-HSCT) in patients with non-Hodgkin lymphoma (NHL). The data source for the modified BEAM regimen was obtained from a prospective, single-arm study (NCT05681403), while the BEAM/BEAC regimen was retrospectively collected from an electronic health record-derived external control group. Primary endpoint was the cumulative incidence of relapse (CIR). Eighty-three patients were included, with 34 in the modified BEAM group, 23 in the BEAM group, and 26 in the BEAC group. The median times were 10.5, 9.0, and 9.0 days for neutrophil engraftment, and 10.5, 10.0, and 10.0 days for platelet engraftment, respectively. Oral mucositis (14.7%, 21.7%, and 7.7%), nausea (8.8%, 17.4%, and 0.0%), and diarrhea (5.9%, 8.2%, and 0.0%) were the most common grade 3-4 non-hematologic toxicities in three groups. No treatment-related death was reported. Besides, no significant differences were observed in 2-year CIR (9.4%, 26.6%, and 23.6%), progression-free survival (90.6%, 73.4%, and 76.4%), and overall survival (97.1%, 87.0%, and 88.5%) rates among three groups (all P > 0.05). The modified BEAM conditioning regimen may have comparable efficacy and safety with the BEAM/BEAC regimen in treating patients with NHL.
{"title":"Comparative efficacy and safety of modified BEAM and BEAM/BEAC as conditioning regimens for autologous hematopoietic stem cell transplantation in patients with non-Hodgkin lymphoma.","authors":"Xiao-Ning Wang, Yu-Qi Wang, Rui-Min Liu, Juan Ren, Hua-Chao Zhu, Peng-Cheng He","doi":"10.1177/09636897251383464","DOIUrl":"10.1177/09636897251383464","url":null,"abstract":"<p><p>This study compared the efficacy and safety of the modified BEAM (mitoxantrone hydrochloride liposome replacing melphalan) versus BEAM/BEAC as a conditioning regimen for autologous hematopoietic stem cell transplantation (auto-HSCT) in patients with non-Hodgkin lymphoma (NHL). The data source for the modified BEAM regimen was obtained from a prospective, single-arm study (NCT05681403), while the BEAM/BEAC regimen was retrospectively collected from an electronic health record-derived external control group. Primary endpoint was the cumulative incidence of relapse (CIR). Eighty-three patients were included, with 34 in the modified BEAM group, 23 in the BEAM group, and 26 in the BEAC group. The median times were 10.5, 9.0, and 9.0 days for neutrophil engraftment, and 10.5, 10.0, and 10.0 days for platelet engraftment, respectively. Oral mucositis (14.7%, 21.7%, and 7.7%), nausea (8.8%, 17.4%, and 0.0%), and diarrhea (5.9%, 8.2%, and 0.0%) were the most common grade 3-4 non-hematologic toxicities in three groups. No treatment-related death was reported. Besides, no significant differences were observed in 2-year CIR (9.4%, 26.6%, and 23.6%), progression-free survival (90.6%, 73.4%, and 76.4%), and overall survival (97.1%, 87.0%, and 88.5%) rates among three groups (all <i>P</i> > 0.05). The modified BEAM conditioning regimen may have comparable efficacy and safety with the BEAM/BEAC regimen in treating patients with NHL.</p>","PeriodicalId":9721,"journal":{"name":"Cell Transplantation","volume":"34 ","pages":"9636897251383464"},"PeriodicalIF":3.2,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12579728/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145408140","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Stroke, a neurological condition from compromised cerebral blood perfusion, remains a major global cause of mortality and disability. Conventional therapies like tissue plasminogen activator are limited by narrow therapeutic windows and potential adverse effects, highlighting the urgency for novel treatments. Stem cell-based therapies, with their neuroprotective and regenerative properties, present a promising yet highly diverse alternative. By conducting literature search and data extraction from the PubMed, Embase, and Cochrane databases, this meta-analysis assessed the clinical efficacy and safety of stem cell-based therapies administered via intravenous (IV) and non-IV routes in 17 studies with stroke patients. Primary outcomes included the National Institute of Health Stroke Scale (NIHSS), Barthel Index (BI), and modified Rankin Scale (mRS), while secondary outcomes included mortality and adverse events. Results demonstrated significant improvements in NIHSS, BI, and mRS scores, particularly in non-IV groups within 6- and 12-month follow-ups, suggesting delayed but enhanced therapeutic efficacy. Mortality was reduced in both IV and non-IV groups, indicating treatment safety. Adverse events, categorized into neurological and systemic complications, showed no significant differences between intervention and control groups, further emphasizing the safety of stem cell therapies. Non-IV routes showed more long-term benefits, potentially due to enhanced cell delivery and integration. These findings demonstrate the potential of stem cell therapies to improve functional recovery and survival in stroke patients, regardless of administration route. However, the delayed response underscores the need for extended follow-up in clinical applications. Further research is required to standardize treatment protocols, optimize cell types and doses, and address patient-specific factors to integrate stem cell therapies into routine clinical practice.
{"title":"Stem Cell-Based Therapies via Different Administration Route for Stroke: A Meta-analysis of Comparative Studies.","authors":"Gabriella Jeanne Mulia, Novelia Anna, John Chung-Che Wu, Hon-Ping Ma, Yung-Hsiao Chiang, Ju-Chi Ou, Kai-Yun Chen","doi":"10.1177/09636897251315121","DOIUrl":"10.1177/09636897251315121","url":null,"abstract":"<p><p>Stroke, a neurological condition from compromised cerebral blood perfusion, remains a major global cause of mortality and disability. Conventional therapies like tissue plasminogen activator are limited by narrow therapeutic windows and potential adverse effects, highlighting the urgency for novel treatments. Stem cell-based therapies, with their neuroprotective and regenerative properties, present a promising yet highly diverse alternative. By conducting literature search and data extraction from the PubMed, Embase, and Cochrane databases, this meta-analysis assessed the clinical efficacy and safety of stem cell-based therapies administered via intravenous (IV) and non-IV routes in 17 studies with stroke patients. Primary outcomes included the National Institute of Health Stroke Scale (NIHSS), Barthel Index (BI), and modified Rankin Scale (mRS), while secondary outcomes included mortality and adverse events. Results demonstrated significant improvements in NIHSS, BI, and mRS scores, particularly in non-IV groups within 6- and 12-month follow-ups, suggesting delayed but enhanced therapeutic efficacy. Mortality was reduced in both IV and non-IV groups, indicating treatment safety. Adverse events, categorized into neurological and systemic complications, showed no significant differences between intervention and control groups, further emphasizing the safety of stem cell therapies. Non-IV routes showed more long-term benefits, potentially due to enhanced cell delivery and integration. These findings demonstrate the potential of stem cell therapies to improve functional recovery and survival in stroke patients, regardless of administration route. However, the delayed response underscores the need for extended follow-up in clinical applications. Further research is required to standardize treatment protocols, optimize cell types and doses, and address patient-specific factors to integrate stem cell therapies into routine clinical practice.</p>","PeriodicalId":9721,"journal":{"name":"Cell Transplantation","volume":"34 ","pages":"9636897251315121"},"PeriodicalIF":3.2,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11808770/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143381712","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01Epub Date: 2025-03-21DOI: 10.1177/09636897251323339
Li Xing, Ronscardy Mondesir, Logan M Glasstetter, Xiang-Yang Zhu, Bo Lu, Mina Al Saeedi, Gurparneet Kaur Sohi, Alfonso Eirin, Lilach O Lerman
Mesenchymal stromal cells (MSCs) possess therapeutic properties, which can be blunted by obesity. Autophagy, a cellular recycling process, is essential for MSC function. We investigated the mechanisms by which obesity affects the properties of MSCs, with a focus on autophagy. Adipose tissue was obtained from kidney donors [body mass index (BMI) <30 kg/m2, non-obese] or individuals undergoing weight loss surgery (BMI ≥30 kg/m2, obese) for MSC harvesting (n = 11 each); samples were randomized to sequencing (seq; n = 5 each) or functional studies (n = 6 each). MSCs were sequenced to determine their epigenetic (5-hydroxymethylcytosine) and transcriptomic profiles across autophagy-related genes using hydroxymethylated DNA immunoprecipitation sequencing and mRNA-seq, respectively. Genes with shared trends in both datasets underwent Reverse Transcription Quantitative Polymerase Chain Reaction (RT-qPCR) validation. During functional studies, 2-h starvation was used to induce autophagy in vitro, enabling detection of changes in the protein expression of microtubule-associated protein 1A/1B-light chain-3 and in autophagic flux. Obesity amplified a starvation-induced reduction in autophagic flux in MSCs while promoting earlier generation of new autophagosomes during autophagy initiation. Integrated analysis of the two sequencing datasets revealed 124 differentially hydroxymethylated genes and 30 differentially expressed mRNAs. Among six overlapping autophagy-related genes, three exhibited same-direction trends. Of these, STX12 and SLC25A4 may be implicated in the impact of obesity on autophagic changes in MSCs. Therefore, human obesity may alter autophagy in adipose tissue-derived MSC, and thereby their metabolism and function.
{"title":"The Impact of Obesity on Autophagy in Human Adipose-Derived Mesenchymal Stromal Cells.","authors":"Li Xing, Ronscardy Mondesir, Logan M Glasstetter, Xiang-Yang Zhu, Bo Lu, Mina Al Saeedi, Gurparneet Kaur Sohi, Alfonso Eirin, Lilach O Lerman","doi":"10.1177/09636897251323339","DOIUrl":"10.1177/09636897251323339","url":null,"abstract":"<p><p>Mesenchymal stromal cells (MSCs) possess therapeutic properties, which can be blunted by obesity. Autophagy, a cellular recycling process, is essential for MSC function. We investigated the mechanisms by which obesity affects the properties of MSCs, with a focus on autophagy. Adipose tissue was obtained from kidney donors [body mass index (BMI) <30 kg/m<sup>2</sup>, non-obese] or individuals undergoing weight loss surgery (BMI ≥30 kg/m<sup>2</sup>, obese) for MSC harvesting (<i>n</i> = 11 each); samples were randomized to sequencing (seq; <i>n</i> = 5 each) or functional studies (<i>n</i> = 6 each). MSCs were sequenced to determine their epigenetic (5-hydroxymethylcytosine) and transcriptomic profiles across autophagy-related genes using hydroxymethylated DNA immunoprecipitation sequencing and mRNA-seq, respectively. Genes with shared trends in both datasets underwent Reverse Transcription Quantitative Polymerase Chain Reaction (RT-qPCR) validation. During functional studies, 2-h starvation was used to induce autophagy <i>in vitro</i>, enabling detection of changes in the protein expression of microtubule-associated protein 1A/1B-light chain-3 and in autophagic flux. Obesity amplified a starvation-induced reduction in autophagic flux in MSCs while promoting earlier generation of new autophagosomes during autophagy initiation. Integrated analysis of the two sequencing datasets revealed 124 differentially hydroxymethylated genes and 30 differentially expressed mRNAs. Among six overlapping autophagy-related genes, three exhibited same-direction trends. Of these, STX12 and SLC25A4 may be implicated in the impact of obesity on autophagic changes in MSCs. Therefore, human obesity may alter autophagy in adipose tissue-derived MSC, and thereby their metabolism and function.</p>","PeriodicalId":9721,"journal":{"name":"Cell Transplantation","volume":"34 ","pages":"9636897251323339"},"PeriodicalIF":3.2,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11930488/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143673284","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01Epub Date: 2025-04-03DOI: 10.1177/09636897251325673
Wenhan Yang, Zhiyu Pan, Jiacheng Zhang, Lian Wang, Ju Lai, Kai Fan, Jingjing Zhu, Qian Liu, Yalei Dai, Jieyu Zhou, Shuhui Wu, Zhengliang Gao, Shaoqing Yu
We previously found that intravenous injection of extracellular vesicles (EVs) from human adipose tissue-derived stem cells (hADSC) could ameliorate allergic rhinitis (AR) in mice through immunomodulatory effects. In clinical trials, nasal delivery has been an attractive treatment for AR. We sought to determine whether there are differences in the therapeutic effects between caudal injection and their combination. We treated AR mice with ADSC-EVs via caudal vein, nasal cavity, or both. After treatment, the mice were re-sensitized and the indices of behavior, nasal mucosa morphology, and cytokine secretion of the mice under different modes of administration were calculated. The resultes show that tail vein, nasal, and combined administration could effectively relieve the inflammatory infiltration of the nasal mucosa of mice, reduce the secretion of IgE, IL-4, and other inflammatory factors, and alleviate the Th1/Th2 imbalance. Injection and nasal delivery, as well as their combination, effectively alleviated the symptoms of rhinitis in mice. Nasal administration has a better therapeutic effect when the inflammatory response is mild. It could be speculated that ADSC-EVs have excellent properties in the treatment of AR, and modes of administration can be selected for different stages of treatment in clinical therapy.
{"title":"Administration Strategy-Dependent Mechanisms and Effects of Human Adipose Tissue Stem Cell Extracellular Vesicles in Mouse Allergic Rhinitis Treatment.","authors":"Wenhan Yang, Zhiyu Pan, Jiacheng Zhang, Lian Wang, Ju Lai, Kai Fan, Jingjing Zhu, Qian Liu, Yalei Dai, Jieyu Zhou, Shuhui Wu, Zhengliang Gao, Shaoqing Yu","doi":"10.1177/09636897251325673","DOIUrl":"10.1177/09636897251325673","url":null,"abstract":"<p><p>We previously found that intravenous injection of extracellular vesicles (EVs) from human adipose tissue-derived stem cells (hADSC) could ameliorate allergic rhinitis (AR) in mice through immunomodulatory effects. In clinical trials, nasal delivery has been an attractive treatment for AR. We sought to determine whether there are differences in the therapeutic effects between caudal injection and their combination. We treated AR mice with ADSC-EVs via caudal vein, nasal cavity, or both. After treatment, the mice were re-sensitized and the indices of behavior, nasal mucosa morphology, and cytokine secretion of the mice under different modes of administration were calculated. The resultes show that tail vein, nasal, and combined administration could effectively relieve the inflammatory infiltration of the nasal mucosa of mice, reduce the secretion of IgE, IL-4, and other inflammatory factors, and alleviate the Th1/Th2 imbalance. Injection and nasal delivery, as well as their combination, effectively alleviated the symptoms of rhinitis in mice. Nasal administration has a better therapeutic effect when the inflammatory response is mild. It could be speculated that ADSC-EVs have excellent properties in the treatment of AR, and modes of administration can be selected for different stages of treatment in clinical therapy.</p>","PeriodicalId":9721,"journal":{"name":"Cell Transplantation","volume":"34 ","pages":"9636897251325673"},"PeriodicalIF":3.2,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11970061/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143779088","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
This study aimed to investigate the impact of human umbilical cord-derived mesenchymal stromal cells (hUC-MSCs) on food allergy (FA) mice induced by ovalbumin. The percentage of regulatory T cells (Tregs) was assessed by administering hUC-MSCs intravenously to FA mouse models with oral challenges, allergic responses and levels of related allergic cytokines. The phenotypes of hUC-MSCs were analysed using flow cytometric analysis. Immunohistochemistry was used for histology observation. Real-time polymerase chain reaction (PCR) was used for gene expression. Jejunum tissue was analysed by transcriptome sequencing. Our results demonstrated that in the current FA model, hUC-MSC therapy significantly alleviated allergic responses and diarrhoea. Levels of immunoglobulin E (IgE), as well as cytokines, such as interleukin (IL)-6 and tumour necrosis factor-α associated with T helper 2 cells, were reduced. Conversely, transforming growth factor (TGF)-β levels increased with hUC-MSC therapy. In addition, enhanced TGF-β expression along with IL-10 messenger ribonucleic acid levels and an increased percentage of CD4+Foxp3+ Tregs were observed. In long-term FA mice models, hUC-MSC therapy exhibited sustained effects in mitigating rectal temperature decrease and mortality rates while reducing the levels of IgE, IL-6 and proportion of IgE+ cells; it also elevated TGF-β levels. Furthermore, hUC-MSC therapy attenuated pathological injury in both current and long-term FA mouse models. Transcriptome sequencing showed that upregulated differentially expressed genes were mainly concentrated in neural activation-ligand interaction, the cyclic guanosine monophosphate-protein kinase G signalling pathway and the TGF-β signalling pathway. The hUC-MSC therapy holds promise for alleviating both immediate and persistent FA conditions; targeting TGF-β and IL-10 secreted by hUC-MSCs may be a potential approach for treating FA.
{"title":"Therapeutic and continuative effects of human umbilical cord-derived mesenchymal stromal cells in food-allergic mice.","authors":"Yuan Zhao, Yabing Ding, Zhaoyan Wang, Qian Wang, Dou Ye, Zuo Luan","doi":"10.1177/09636897251326899","DOIUrl":"10.1177/09636897251326899","url":null,"abstract":"<p><p>This study aimed to investigate the impact of human umbilical cord-derived mesenchymal stromal cells (hUC-MSCs) on food allergy (FA) mice induced by ovalbumin. The percentage of regulatory T cells (Tregs) was assessed by administering hUC-MSCs intravenously to FA mouse models with oral challenges, allergic responses and levels of related allergic cytokines. The phenotypes of hUC-MSCs were analysed using flow cytometric analysis. Immunohistochemistry was used for histology observation. Real-time polymerase chain reaction (PCR) was used for gene expression. Jejunum tissue was analysed by transcriptome sequencing. Our results demonstrated that in the current FA model, hUC-MSC therapy significantly alleviated allergic responses and diarrhoea. Levels of immunoglobulin E (IgE), as well as cytokines, such as interleukin (IL)-6 and tumour necrosis factor-α associated with T helper 2 cells, were reduced. Conversely, transforming growth factor (TGF)-β levels increased with hUC-MSC therapy. In addition, enhanced TGF-β expression along with IL-10 messenger ribonucleic acid levels and an increased percentage of CD4<sup>+</sup>Foxp3<sup>+</sup> Tregs were observed. In long-term FA mice models, hUC-MSC therapy exhibited sustained effects in mitigating rectal temperature decrease and mortality rates while reducing the levels of IgE, IL-6 and proportion of IgE+ cells; it also elevated TGF-β levels. Furthermore, hUC-MSC therapy attenuated pathological injury in both current and long-term FA mouse models. Transcriptome sequencing showed that upregulated differentially expressed genes were mainly concentrated in neural activation-ligand interaction, the cyclic guanosine monophosphate-protein kinase G signalling pathway and the TGF-β signalling pathway. The hUC-MSC therapy holds promise for alleviating both immediate and persistent FA conditions; targeting TGF-β and IL-10 secreted by hUC-MSCs may be a potential approach for treating FA.</p>","PeriodicalId":9721,"journal":{"name":"Cell Transplantation","volume":"34 ","pages":"9636897251326899"},"PeriodicalIF":3.2,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11951882/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143718085","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Leucine-rich repeat-containing G-protein-coupled receptors regulate stem cell activity and tissue homeostasis within female reproductive organs, primarily through their interaction with the Wnt/β-catenin signaling pathway. LGR4-6 are increasingly recognized for their roles in organ development, regeneration, and cancer. This review aims to provide a comprehensive overview of the roles of LGR4-6 in female reproductive organs, highlighting their significance in normal physiology and disease states, specifically in the context of ovarian cancer. LGR4 is essential for the proper development of the female reproductive system; its deficiency leads to significant reproductive abnormalities, including delayed menarche and follicle development issues. LGR5 is a well-established marker of stem cells in the ovary and fallopian tubes. It has been implicated in the pathogenesis of high-grade serous ovarian cancer. LGR6, while less studied, shares functional similarities with LGR5 and can maintain stemness. It contributes to chemoresistance in ovarian cancer. LGR6 is a marker for fallopian tube stem cells and is involved in stem cell maintenance and differentiation. LGR4-6 regulate the pathophysiology of female reproductive tissues. LGR4-6 are promising therapeutic targets for treating reproductive cancers and other related disorders. Molecular mechanisms underlying the functions of LGR4-6 should be studied.
{"title":"Role of Leucine-Rich Repeat-Containing G-Protein-Coupled Receptors 4-6 (LGR4-6) in the Ovary and Other Female Reproductive Organs: A Literature Review.","authors":"Yu-Hsun Chang, Kun-Chi Wu, Kai-Hung Wang, Dah-Ching Ding","doi":"10.1177/09636897241303441","DOIUrl":"10.1177/09636897241303441","url":null,"abstract":"<p><p>Leucine-rich repeat-containing G-protein-coupled receptors regulate stem cell activity and tissue homeostasis within female reproductive organs, primarily through their interaction with the Wnt/β-catenin signaling pathway. LGR4-6 are increasingly recognized for their roles in organ development, regeneration, and cancer. This review aims to provide a comprehensive overview of the roles of LGR4-6 in female reproductive organs, highlighting their significance in normal physiology and disease states, specifically in the context of ovarian cancer. LGR4 is essential for the proper development of the female reproductive system; its deficiency leads to significant reproductive abnormalities, including delayed menarche and follicle development issues. LGR5 is a well-established marker of stem cells in the ovary and fallopian tubes. It has been implicated in the pathogenesis of high-grade serous ovarian cancer. LGR6, while less studied, shares functional similarities with LGR5 and can maintain stemness. It contributes to chemoresistance in ovarian cancer. LGR6 is a marker for fallopian tube stem cells and is involved in stem cell maintenance and differentiation. LGR4-6 regulate the pathophysiology of female reproductive tissues. LGR4-6 are promising therapeutic targets for treating reproductive cancers and other related disorders. Molecular mechanisms underlying the functions of LGR4-6 should be studied.</p>","PeriodicalId":9721,"journal":{"name":"Cell Transplantation","volume":"34 ","pages":"9636897241303441"},"PeriodicalIF":3.2,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11776010/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143057898","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}