Pub Date : 2022-12-24DOI: 10.1038/s41536-022-00271-2
Anne L Plant, Nicole Piscopo, Krishanu Saha, Claudia Zylberberg, Krishnendu Roy, Katherine Tsokas, Samantha N Schumm, Sarah H Beachy
{"title":"Implementing systems thinking and data science in the training of the regenerative medicine workforce.","authors":"Anne L Plant, Nicole Piscopo, Krishanu Saha, Claudia Zylberberg, Krishnendu Roy, Katherine Tsokas, Samantha N Schumm, Sarah H Beachy","doi":"10.1038/s41536-022-00271-2","DOIUrl":"https://doi.org/10.1038/s41536-022-00271-2","url":null,"abstract":"","PeriodicalId":54236,"journal":{"name":"npj Regenerative Medicine","volume":null,"pages":null},"PeriodicalIF":7.2,"publicationDate":"2022-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9790008/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10453323","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Reconstruction of complex cartilage defects has remained a great challenge for tissue engineering due to the lack of stem cells and chronic inflammation within the joint. In this study, we have developed an injectable pig cartilage-derived decellularized extracellular matrix (dECM) hydrogels for the repair of cartilage defects, which has shown sound biocompatibility and immunomodulatory capacity both in vitro and in vivo. The dECM hydrogels can enhance the chondrogenic differentiation of human urine-derived stem cells (USCs). As shown by in vitro experiment, the USCs in the dECM hydrogels have survived, proliferated, and produced a mass of cartilage-specific extracellular matrix containing collagen II and aggrecan. And the USCs-laden dECM hydrogels have shown the capacity to promote the secretion of extracellular matrix, modulate the immune response and promote cartilage regeneration in the rat model for cartilage defect.
{"title":"Injectable decellularized cartilage matrix hydrogel encapsulating urine-derived stem cells for immunomodulatory and cartilage defect regeneration.","authors":"Junfeng Zeng, Liping Huang, Huazhang Xiong, Qianjin Li, Chenyu Wu, Yizhou Huang, Huiqi Xie, Bin Shen","doi":"10.1038/s41536-022-00269-w","DOIUrl":"https://doi.org/10.1038/s41536-022-00269-w","url":null,"abstract":"<p><p>Reconstruction of complex cartilage defects has remained a great challenge for tissue engineering due to the lack of stem cells and chronic inflammation within the joint. In this study, we have developed an injectable pig cartilage-derived decellularized extracellular matrix (dECM) hydrogels for the repair of cartilage defects, which has shown sound biocompatibility and immunomodulatory capacity both in vitro and in vivo. The dECM hydrogels can enhance the chondrogenic differentiation of human urine-derived stem cells (USCs). As shown by in vitro experiment, the USCs in the dECM hydrogels have survived, proliferated, and produced a mass of cartilage-specific extracellular matrix containing collagen II and aggrecan. And the USCs-laden dECM hydrogels have shown the capacity to promote the secretion of extracellular matrix, modulate the immune response and promote cartilage regeneration in the rat model for cartilage defect.</p>","PeriodicalId":54236,"journal":{"name":"npj Regenerative Medicine","volume":null,"pages":null},"PeriodicalIF":7.2,"publicationDate":"2022-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9780205/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10424635","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-12-17DOI: 10.1038/s41536-022-00268-x
Xin Zhong, Tao-Tao Tang, An-Ran Shen, Jing-Yuan Cao, Jing Jing, Cui Wang, Xiao-Xiao Zhu, Yi Wen, Zuo-Lin Li, Bin Wang, Suo-Fu Qin, Bi-Cheng Liu, Lin-Li Lv
Peritubular capillaries (PTCs) are closely related to renal tubules in structure and function, and both are pivotal regulators in the development and progression of acute kidney injury (AKI). However, the mechanisms that underlie the interaction between PTCs and tubules during AKI remain unclear. Here we explored a new mode of tubulovascular crosstalk mediated by small extracellular vesicles (sEV) after AKI. In response to renal ischemia/reperfusion (I/R) injury, endothelial proliferation of PTCs and tubular expression of vascular endothelial growth factor-A (VEGF-A) were increased, accompanied by a remarkable redistribution of cytoplasmic VEGF-A to the basolateral side of tubular cells. Meanwhile, the secretion mode of VEGF-A was converted in the injured tubular cells, which showed a much greater tendency to secrete VEGF-A via sEV other than the free form. Interestingly, tubular cell-derived VEGF-A-enriched sEV (sEV-VEGF-A) turned out to promote endothelial proliferation which was regulated by VEGF receptors 1 and 2. Furthermore, inhibition of renal sEV secretion by Rab27a knockdown resulted in a significant decrease in the proliferation of peritubular endothelial cells in vivo. Importantly, taking advantage of the newly recognized endogenous repair response of PTCs, exogenous supplementation of VEGF-A + sEV efficiently recused PTC rarefaction, improved renal perfusion, and halted the AKI to CKD transition. Taken together, our study uncovered a novel intrinsic repair response after AKI through renal tubule-PTC crosstalk via sEV-VEGF-A, which could be exploited as a promising therapeutic angiogenesis strategy in diseases with ischemia.
小管周围毛细血管(ptc)在结构和功能上与肾小管密切相关,两者都是急性肾损伤(AKI)发生和进展的关键调节因子。然而,AKI期间ptc和小管相互作用的机制尚不清楚。本研究探讨了AKI后由细胞外小泡(sEV)介导的管-血管串扰的新模式。肾缺血再灌注(I/R)损伤后,ptc内皮细胞增殖增加,血管内皮生长因子- a (VEGF-A)表达增加,细胞质VEGF-A向肾小管细胞基底外侧重新分布。同时,VEGF-A的分泌方式在损伤小管细胞中发生了转变,其通过sEV而非自由形式分泌VEGF-A的倾向要大得多。有趣的是,小管细胞衍生的富含VEGF- a的sEV (sEV-VEGF- a)被证明可以促进内皮细胞的增殖,这是由VEGF受体1和2调节的。此外,通过敲低Rab27a抑制肾sEV分泌,导致体内小管周围内皮细胞的增殖显著减少。重要的是,利用新近认识到的PTC的内源性修复反应,外源性补充VEGF-A + sEV有效地避免了PTC的稀释,改善了肾脏灌注,并阻止了AKI向CKD的过渡。综上所述,我们的研究揭示了肾小管- ptc通过sEV-VEGF-A串扰在AKI后产生的一种新的内在修复反应,这可能是一种有前途的治疗缺血疾病的血管生成策略。
{"title":"Tubular epithelial cells-derived small extracellular vesicle-VEGF-A promotes peritubular capillary repair in ischemic kidney injury.","authors":"Xin Zhong, Tao-Tao Tang, An-Ran Shen, Jing-Yuan Cao, Jing Jing, Cui Wang, Xiao-Xiao Zhu, Yi Wen, Zuo-Lin Li, Bin Wang, Suo-Fu Qin, Bi-Cheng Liu, Lin-Li Lv","doi":"10.1038/s41536-022-00268-x","DOIUrl":"https://doi.org/10.1038/s41536-022-00268-x","url":null,"abstract":"<p><p>Peritubular capillaries (PTCs) are closely related to renal tubules in structure and function, and both are pivotal regulators in the development and progression of acute kidney injury (AKI). However, the mechanisms that underlie the interaction between PTCs and tubules during AKI remain unclear. Here we explored a new mode of tubulovascular crosstalk mediated by small extracellular vesicles (sEV) after AKI. In response to renal ischemia/reperfusion (I/R) injury, endothelial proliferation of PTCs and tubular expression of vascular endothelial growth factor-A (VEGF-A) were increased, accompanied by a remarkable redistribution of cytoplasmic VEGF-A to the basolateral side of tubular cells. Meanwhile, the secretion mode of VEGF-A was converted in the injured tubular cells, which showed a much greater tendency to secrete VEGF-A via sEV other than the free form. Interestingly, tubular cell-derived VEGF-A-enriched sEV (sEV-VEGF-A) turned out to promote endothelial proliferation which was regulated by VEGF receptors 1 and 2. Furthermore, inhibition of renal sEV secretion by Rab27a knockdown resulted in a significant decrease in the proliferation of peritubular endothelial cells in vivo. Importantly, taking advantage of the newly recognized endogenous repair response of PTCs, exogenous supplementation of VEGF-A + sEV efficiently recused PTC rarefaction, improved renal perfusion, and halted the AKI to CKD transition. Taken together, our study uncovered a novel intrinsic repair response after AKI through renal tubule-PTC crosstalk via sEV-VEGF-A, which could be exploited as a promising therapeutic angiogenesis strategy in diseases with ischemia.</p>","PeriodicalId":54236,"journal":{"name":"npj Regenerative Medicine","volume":null,"pages":null},"PeriodicalIF":7.2,"publicationDate":"2022-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9759551/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10403893","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Allogeneic cell therapies are not fully effective in treating osteoarthritis of the knee (OAK). We recently reported that transplantation of autologous chondrocyte cell-sheets along with open-wedge high tibial osteotomy promoted hyaline cartilage repair in humans. Here we describe our regenerative therapy for OAK using polydactyly-derived allogeneic chondrocyte cell-sheets (PD sheets) and temperature-responsive culture inserts. Ten patients with OAK and cartilage defects categorized arthroscopically as Outerbridge grade III or IV received the therapy. Cartilage viscoelasticity and thickness were assessed before and after transplantation. Arthroscopic biopsies obtained 12 months after transplantation were analyzed histologically. Gene expression was analyzed to evaluate the PD sheets. In this small initial longitudinal series, PD sheet transplantation was effective in treating OAK, as indicated by changes in cartilage properties. Gene marker sets in PD sheets may predict outcomes after therapy and provide markers for the selection of donor cells. This combined surgery may be an ideal regenerative therapy with disease-modifying effects in OAK patients.
{"title":"Polydactyly-derived allogeneic chondrocyte cell-sheet transplantation with high tibial osteotomy as regenerative therapy for knee osteoarthritis.","authors":"Kosuke Hamahashi, Eriko Toyoda, Miya Ishihara, Genya Mitani, Tomonori Takagaki, Nagatoshi Kaneshiro, Miki Maehara, Takumi Takahashi, Eri Okada, Ayako Watanabe, Yoshihiko Nakamura, Reiko Kato, Ryo Matoba, Takehiko Takagi, Hidenori Akutsu, Akihiro Umezawa, Hiroyuki Kobayashi, Tadashi Akamatsu, Masayuki Yamato, Teruo Okano, Masahiko Watanabe, Masato Sato","doi":"10.1038/s41536-022-00272-1","DOIUrl":"https://doi.org/10.1038/s41536-022-00272-1","url":null,"abstract":"<p><p>Allogeneic cell therapies are not fully effective in treating osteoarthritis of the knee (OAK). We recently reported that transplantation of autologous chondrocyte cell-sheets along with open-wedge high tibial osteotomy promoted hyaline cartilage repair in humans. Here we describe our regenerative therapy for OAK using polydactyly-derived allogeneic chondrocyte cell-sheets (PD sheets) and temperature-responsive culture inserts. Ten patients with OAK and cartilage defects categorized arthroscopically as Outerbridge grade III or IV received the therapy. Cartilage viscoelasticity and thickness were assessed before and after transplantation. Arthroscopic biopsies obtained 12 months after transplantation were analyzed histologically. Gene expression was analyzed to evaluate the PD sheets. In this small initial longitudinal series, PD sheet transplantation was effective in treating OAK, as indicated by changes in cartilage properties. Gene marker sets in PD sheets may predict outcomes after therapy and provide markers for the selection of donor cells. This combined surgery may be an ideal regenerative therapy with disease-modifying effects in OAK patients.</p>","PeriodicalId":54236,"journal":{"name":"npj Regenerative Medicine","volume":null,"pages":null},"PeriodicalIF":7.2,"publicationDate":"2022-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9755241/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10714318","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-12-16DOI: 10.1038/s41536-022-00264-1
Francesca Boscolo Sesillo, Varsha Rajesh, Michelle Wong, Pamela Duran, John B Rudell, Courtney P Rundio, Brittni B Baynes, Louise C Laurent, Alessandra Sacco, Karen L Christman, Marianna Alperin
Pelvic floor muscle (PFM) injury during childbirth is a key risk factor for pelvic floor disorders that affect millions of women worldwide. Muscle stem cells (MuSCs), supported by the fibro-adipogenic progenitors (FAPs) and immune cells, are indispensable for the regeneration of injured appendicular skeletal muscles. However, almost nothing is known about their role in PFM regeneration following birth injury. To elucidate the role of MuSCs, FAPs, and immune infiltrate in this context, we used radiation to perturb cell function and followed PFM recovery in a validated simulated birth injury (SBI) rat model. Non-irradiated and irradiated rats were euthanized at 3,7,10, and 28 days post-SBI (dpi). Twenty-eight dpi, PFM fiber cross-sectional area (CSA) was significantly lower and the extracellular space occupied by immune infiltrate was larger in irradiated relative to nonirradiated injured animals. Following SBI in non-irradiated animals, MuSCs and FAPs expanded significantly at 7 and 3 dpi, respectively; this expansion did not occur in irradiated animals at the same time points. At 7 and 10 dpi, we observed persistent immune response in PFMs subjected to irradiation compared to non-irradiated injured PFMs. CSA of newly regenerated fibers was also significantly smaller following SBI in irradiated compared to non-irradiated injured PFMs. Our results demonstrate that the loss of function and decreased expansion of MuSCs and FAPs after birth injury lead to impaired PFM recovery. These findings form the basis for further studies focused on the identification of novel therapeutic targets to counteract postpartum PFM dysfunction and the associated pelvic floor disorders.
{"title":"Muscle stem cells and fibro-adipogenic progenitors in female pelvic floor muscle regeneration following birth injury.","authors":"Francesca Boscolo Sesillo, Varsha Rajesh, Michelle Wong, Pamela Duran, John B Rudell, Courtney P Rundio, Brittni B Baynes, Louise C Laurent, Alessandra Sacco, Karen L Christman, Marianna Alperin","doi":"10.1038/s41536-022-00264-1","DOIUrl":"10.1038/s41536-022-00264-1","url":null,"abstract":"<p><p>Pelvic floor muscle (PFM) injury during childbirth is a key risk factor for pelvic floor disorders that affect millions of women worldwide. Muscle stem cells (MuSCs), supported by the fibro-adipogenic progenitors (FAPs) and immune cells, are indispensable for the regeneration of injured appendicular skeletal muscles. However, almost nothing is known about their role in PFM regeneration following birth injury. To elucidate the role of MuSCs, FAPs, and immune infiltrate in this context, we used radiation to perturb cell function and followed PFM recovery in a validated simulated birth injury (SBI) rat model. Non-irradiated and irradiated rats were euthanized at 3,7,10, and 28 days post-SBI (dpi). Twenty-eight dpi, PFM fiber cross-sectional area (CSA) was significantly lower and the extracellular space occupied by immune infiltrate was larger in irradiated relative to nonirradiated injured animals. Following SBI in non-irradiated animals, MuSCs and FAPs expanded significantly at 7 and 3 dpi, respectively; this expansion did not occur in irradiated animals at the same time points. At 7 and 10 dpi, we observed persistent immune response in PFMs subjected to irradiation compared to non-irradiated injured PFMs. CSA of newly regenerated fibers was also significantly smaller following SBI in irradiated compared to non-irradiated injured PFMs. Our results demonstrate that the loss of function and decreased expansion of MuSCs and FAPs after birth injury lead to impaired PFM recovery. These findings form the basis for further studies focused on the identification of novel therapeutic targets to counteract postpartum PFM dysfunction and the associated pelvic floor disorders.</p>","PeriodicalId":54236,"journal":{"name":"npj Regenerative Medicine","volume":null,"pages":null},"PeriodicalIF":6.4,"publicationDate":"2022-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9758192/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10117633","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-12-09DOI: 10.1038/s41536-022-00266-z
Katherine H Griffin, Shierly W Fok, J Kent Leach
Cell therapies offer a tailorable, personalized treatment for use in tissue engineering to address defects arising from trauma, inefficient wound repair, or congenital malformation. However, most cell therapies have achieved limited success to date. Typically injected in solution as monodispersed cells, transplanted cells exhibit rapid cell death or insufficient retention at the site, thereby limiting their intended effects to only a few days. Spheroids, which are dense, three-dimensional (3D) aggregates of cells, enhance the beneficial effects of cell therapies by increasing and prolonging cell-cell and cell-matrix signaling. The use of spheroids is currently under investigation for many cell types. Among cells under evaluation, spheroids formed of mesenchymal stromal cells (MSCs) are particularly promising. MSC spheroids not only exhibit increased cell survival and retained differentiation, but they also secrete a potent secretome that promotes angiogenesis, reduces inflammation, and attracts endogenous host cells to promote tissue regeneration and repair. However, the clinical translation of spheroids has lagged behind promising preclinical outcomes due to hurdles in their formation, instruction, and use that have yet to be overcome. This review will describe the current state of preclinical spheroid research and highlight two key examples of spheroid use in clinically relevant disease modeling. It will highlight techniques used to instruct the phenotype and function of spheroids, describe current limitations to their use, and offer suggestions for the effective translation of cell spheroids for therapeutic treatments.
{"title":"Strategies to capitalize on cell spheroid therapeutic potential for tissue repair and disease modeling.","authors":"Katherine H Griffin, Shierly W Fok, J Kent Leach","doi":"10.1038/s41536-022-00266-z","DOIUrl":"10.1038/s41536-022-00266-z","url":null,"abstract":"<p><p>Cell therapies offer a tailorable, personalized treatment for use in tissue engineering to address defects arising from trauma, inefficient wound repair, or congenital malformation. However, most cell therapies have achieved limited success to date. Typically injected in solution as monodispersed cells, transplanted cells exhibit rapid cell death or insufficient retention at the site, thereby limiting their intended effects to only a few days. Spheroids, which are dense, three-dimensional (3D) aggregates of cells, enhance the beneficial effects of cell therapies by increasing and prolonging cell-cell and cell-matrix signaling. The use of spheroids is currently under investigation for many cell types. Among cells under evaluation, spheroids formed of mesenchymal stromal cells (MSCs) are particularly promising. MSC spheroids not only exhibit increased cell survival and retained differentiation, but they also secrete a potent secretome that promotes angiogenesis, reduces inflammation, and attracts endogenous host cells to promote tissue regeneration and repair. However, the clinical translation of spheroids has lagged behind promising preclinical outcomes due to hurdles in their formation, instruction, and use that have yet to be overcome. This review will describe the current state of preclinical spheroid research and highlight two key examples of spheroid use in clinically relevant disease modeling. It will highlight techniques used to instruct the phenotype and function of spheroids, describe current limitations to their use, and offer suggestions for the effective translation of cell spheroids for therapeutic treatments.</p>","PeriodicalId":54236,"journal":{"name":"npj Regenerative Medicine","volume":null,"pages":null},"PeriodicalIF":6.4,"publicationDate":"2022-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9734656/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10328302","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-12-08DOI: 10.1038/s41536-022-00265-0
Pei Shen, Lu Chen, Dahe Zhang, Simo Xia, Zhuman Lv, Duohong Zou, Zhiyuan Zhang, Chi Yang, Wenlin Li
Articular cartilage is highly specific and has limited capacity for regeneration if damaged. Human pluripotent stem cells (hPSCs) have the potential to generate any cell type in the body. Here, we report the dual-phase induction of ectodermal chondrogenic cells (ECCs) from hPSCs through the neural crest (NC). ECCs were able to self-renew long-term (over numerous passages) in a cocktail of growth factors and small molecules. The cells stably expressed cranial neural crest-derived mandibular condylar cartilage markers, such as MSX1, FOXC1 and FOXC2. Compared with chondroprogenitors from iPSCs via the paraxial mesoderm, ECCs had single-cell transcriptome profiles similar to condylar chondrocytes. After the removal of the cocktail sustaining self-renewal, the cells stopped proliferating and differentiated into a homogenous chondrocyte population. Remarkably, after transplantation, this cell lineage was able to form cartilage-like structures resembling mandibular condylar cartilage in vivo. This finding provides a framework to generate self-renewing cranial chondrogenic progenitors, which could be useful for developing cell-based therapy for cranial cartilage injury.
{"title":"Rapid induction and long-term self-renewal of neural crest-derived ectodermal chondrogenic cells from hPSCs.","authors":"Pei Shen, Lu Chen, Dahe Zhang, Simo Xia, Zhuman Lv, Duohong Zou, Zhiyuan Zhang, Chi Yang, Wenlin Li","doi":"10.1038/s41536-022-00265-0","DOIUrl":"https://doi.org/10.1038/s41536-022-00265-0","url":null,"abstract":"<p><p>Articular cartilage is highly specific and has limited capacity for regeneration if damaged. Human pluripotent stem cells (hPSCs) have the potential to generate any cell type in the body. Here, we report the dual-phase induction of ectodermal chondrogenic cells (ECCs) from hPSCs through the neural crest (NC). ECCs were able to self-renew long-term (over numerous passages) in a cocktail of growth factors and small molecules. The cells stably expressed cranial neural crest-derived mandibular condylar cartilage markers, such as MSX1, FOXC1 and FOXC2. Compared with chondroprogenitors from iPSCs via the paraxial mesoderm, ECCs had single-cell transcriptome profiles similar to condylar chondrocytes. After the removal of the cocktail sustaining self-renewal, the cells stopped proliferating and differentiated into a homogenous chondrocyte population. Remarkably, after transplantation, this cell lineage was able to form cartilage-like structures resembling mandibular condylar cartilage in vivo. This finding provides a framework to generate self-renewing cranial chondrogenic progenitors, which could be useful for developing cell-based therapy for cranial cartilage injury.</p>","PeriodicalId":54236,"journal":{"name":"npj Regenerative Medicine","volume":null,"pages":null},"PeriodicalIF":7.2,"publicationDate":"2022-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9729200/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10333684","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-11-23DOI: 10.1038/s41536-022-00263-2
Lin Gong, Nanfang Nie, Xilin Shen, Jingwei Zhang, Yu Li, Yixiao Liu, Jiaqi Xu, Wei Jiang, Yanshan Liu, Hua Liu, Bingbing Wu, XiaoHui Zou
Stem cell-based tissue regeneration strategies are promising treatments for severe endometrial injuries. However, there are few appropriate seed cells for regenerating a full-thickness endometrium, which mainly consists of epithelia and stroma. Müllerian ducts in female embryonic development develop into endometrial epithelia and stroma. Hence, we first generated human pluripotent stem cells (hPSC)-derived Müllerian duct-like cells (MDLCs) using a defined and effective protocol. The MDLCs are bi-potent, can gradually differentiate into endometrial epithelial and stromal cells, and reconstitute full-thickness endometrium in vitro and in vivo. Furthermore, MDLCs showed the in situ repair capabilities of reconstructing endometrial structure and recovering pregnancy function in full-thickness endometrial injury rats, and their differentiation fate was revealed by single-cell RNA sequencing (scRNA-seq). Our study provides a strategy for hPSC differentiation into endometrial lineages and an alternative seed cell for injured endometrial regeneration.
{"title":"Bi-potential hPSC-derived Müllerian duct-like cells for full-thickness and functional endometrium regeneration.","authors":"Lin Gong, Nanfang Nie, Xilin Shen, Jingwei Zhang, Yu Li, Yixiao Liu, Jiaqi Xu, Wei Jiang, Yanshan Liu, Hua Liu, Bingbing Wu, XiaoHui Zou","doi":"10.1038/s41536-022-00263-2","DOIUrl":"https://doi.org/10.1038/s41536-022-00263-2","url":null,"abstract":"<p><p>Stem cell-based tissue regeneration strategies are promising treatments for severe endometrial injuries. However, there are few appropriate seed cells for regenerating a full-thickness endometrium, which mainly consists of epithelia and stroma. Müllerian ducts in female embryonic development develop into endometrial epithelia and stroma. Hence, we first generated human pluripotent stem cells (hPSC)-derived Müllerian duct-like cells (MDLCs) using a defined and effective protocol. The MDLCs are bi-potent, can gradually differentiate into endometrial epithelial and stromal cells, and reconstitute full-thickness endometrium in vitro and in vivo. Furthermore, MDLCs showed the in situ repair capabilities of reconstructing endometrial structure and recovering pregnancy function in full-thickness endometrial injury rats, and their differentiation fate was revealed by single-cell RNA sequencing (scRNA-seq). Our study provides a strategy for hPSC differentiation into endometrial lineages and an alternative seed cell for injured endometrial regeneration.</p>","PeriodicalId":54236,"journal":{"name":"npj Regenerative Medicine","volume":null,"pages":null},"PeriodicalIF":7.2,"publicationDate":"2022-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9684429/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40702832","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-11-04DOI: 10.1038/s41536-022-00262-3
Selina Wrublewsky, Andrea Weinzierl, Isabelle Hornung, Leticia Prates-Roma, Michael D Menger, Matthias W Laschke, Emmanuel Ampofo
Insufficient revascularization of pancreatic islets is one of the major obstacles impairing the success of islet transplantation. To overcome this problem, we introduce in the present study a straightforward strategy to accelerate the engraftment of isolated islets. For this purpose, we co-transplanted 250 islets and 20,000 adipose tissue-derived microvascular fragments (MVF) from donor mice under the kidney capsule as well as 500 or 1000 islets with 40,000 MVF into the subcutaneous space of diabetic mice. We found that the co-transplantation of islets and MVF markedly accelerates the restoration of normoglycemia in diabetic recipients compared with the transplantation of islets alone. In fact, the transplantation of 250 islets with 20,000 MVF under the kidney capsule reversed diabetes in 88% of mice and the subcutaneous transplantation of 500 or 1000 islets with 40,000 MVF restored normoglycemia in 100% of mice. Moreover, diabetic mice receiving islets and MVF exhibited plasma insulin levels similar to nondiabetic control animals. Additional immunohistochemical analyses of the grafts revealed a significantly higher number of islet cells and microvessels in the co-transplantation groups. These findings demonstrate that the co-transplantation of islets and MVF is a promising strategy to improve the success rates of islet transplantation, which could be easily implemented into future clinical practice.
{"title":"Co-transplantation of pancreatic islets and microvascular fragments effectively restores normoglycemia in diabetic mice.","authors":"Selina Wrublewsky, Andrea Weinzierl, Isabelle Hornung, Leticia Prates-Roma, Michael D Menger, Matthias W Laschke, Emmanuel Ampofo","doi":"10.1038/s41536-022-00262-3","DOIUrl":"https://doi.org/10.1038/s41536-022-00262-3","url":null,"abstract":"<p><p>Insufficient revascularization of pancreatic islets is one of the major obstacles impairing the success of islet transplantation. To overcome this problem, we introduce in the present study a straightforward strategy to accelerate the engraftment of isolated islets. For this purpose, we co-transplanted 250 islets and 20,000 adipose tissue-derived microvascular fragments (MVF) from donor mice under the kidney capsule as well as 500 or 1000 islets with 40,000 MVF into the subcutaneous space of diabetic mice. We found that the co-transplantation of islets and MVF markedly accelerates the restoration of normoglycemia in diabetic recipients compared with the transplantation of islets alone. In fact, the transplantation of 250 islets with 20,000 MVF under the kidney capsule reversed diabetes in 88% of mice and the subcutaneous transplantation of 500 or 1000 islets with 40,000 MVF restored normoglycemia in 100% of mice. Moreover, diabetic mice receiving islets and MVF exhibited plasma insulin levels similar to nondiabetic control animals. Additional immunohistochemical analyses of the grafts revealed a significantly higher number of islet cells and microvessels in the co-transplantation groups. These findings demonstrate that the co-transplantation of islets and MVF is a promising strategy to improve the success rates of islet transplantation, which could be easily implemented into future clinical practice.</p>","PeriodicalId":54236,"journal":{"name":"npj Regenerative Medicine","volume":null,"pages":null},"PeriodicalIF":7.2,"publicationDate":"2022-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9636251/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40466934","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}