Differences in the intrinsic chondrogenic potential of human mesenchymal stromal cells and iPSC-derived multipotent cells.
Differences in the intrinsic chondrogenic potential of human mesenchymal stromal cells and iPSC-derived multipotent cells.
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DOI：
10.1002/ctm2.1112
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发表时间：
2022-12
影响因子：
10.6
通讯作者：
中科院分区：
文献类型：
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由诱导多能干细胞（iPSCs）产生的人多能祖细胞（hiMPCs）是软骨再生的一种新的细胞来源。在大多数研究中，骨形态发生蛋白（BMPs）是促进转化生长因子β (TGFβ)诱导的hiMPC软骨形成所必需的。相反，tgf - β本身就足以导致人原发性间充质间质细胞（hMSCs）强健的软骨形成。目前，hiMPCs和hMSCs之间这种差异的机制尚未完全了解。在这项研究中，我们首先测试了不同的生长因子单独或联合刺激hiMPC软骨形成，特别关注软骨细胞肥大。在大鼠骨软骨缺损模型中评估了hiMPCs衍生软骨的修复能力。从骨髓中分离的hMSCs作为对照纳入所有研究。最后，进行了一项机制研究，以了解为什么hiMPCs和hMSCs对tgf - β的反应不同。含tgf - β3和BMP6的成软骨培养基可使hiMPCs在体外形成健壮的软骨，并伴有轻微的肥大。这种新方法产生的软骨组织在皮下植入后能够抵抗成骨转变，并在大鼠骨软骨缺损中产生透明软骨样再生。有趣的是，tgf - β3诱导了hMSCs中Smad2/3和Smad1/5的磷酸化，但仅激活了hiMPCs中的Smad2/3。补充BMP6激活Smad1/5，显著增强TGFβ诱导hiMPC软骨形成的能力。BMP6促进软骨生成的功能被BMP通路抑制剂所消除。本研究描述了一种从低肥厚的hiMPCs生成软骨细胞用于透明软骨修复的稳健方法，并阐明了hMSCs和hiMPCs对tgf - β反应的差异。我们的研究结果还表明，激活Smad2/3和Smad1/5在软骨形成起始中的重要性。Smad1/5的激活对于启动由人诱导多能干细胞（iPSCs）产生的多能祖细胞（iMPCs）的软骨形成至关重要。随着传代次数的增加，iMPCs的软骨形成能力迅速下降。当在添加tgf - β3和BMP6的培养基中进行微球培养时，iMPCs可以产生具有最小软骨细胞肥大表型的透明样软骨。
Human multipotent progenitor cells (hiMPCs) created from induced pluripotent stem cells (iPSCs) represent a new cell source for cartilage regeneration. In most studies, bone morphogenetic proteins (BMPs) are needed to enhance transforming growth factor‐β (TGFβ)‐induced hiMPC chondrogenesis. In contrast, TGFβ alone is sufficient to result in robust chondrogenesis of human primary mesenchymal stromal cells (hMSCs). Currently, the mechanism underlying this difference between hiMPCs and hMSCs has not been fully understood. In this study, we first tested different growth factors alone or in combination in stimulating hiMPC chondrogenesis, with a special focus on chondrocytic hypertrophy. The reparative capacity of hiMPCs‐derived cartilage was assessed in an osteochondral defect model created in rats. hMSCs isolated from bone marrow were included in all studies as the control. Lastly, a mechanistic study was conducted to understand why hiMPCs and hMSCs behave differently in responding to TGFβ. Chondrogenic medium supplemented with TGFβ3 and BMP6 led to robust in vitro cartilage formation from hiMPCs with minimal hypertrophy. Cartilage tissue generated from this new method was resistant to osteogenic transition upon subcutaneous implantation and resulted in a hyaline cartilage‐like regeneration in osteochondral defects in rats. Interestingly, TGFβ3 induced phosphorylation of both Smad2/3 and Smad1/5 in hMSCs, but only activated Smad2/3 in hiMPCs. Supplementing BMP6 activated Smad1/5 and significantly enhanced TGFβ’s compacity in inducing hiMPC chondrogenesis. The chondro‐promoting function of BMP6 was abolished by the treatment of a BMP pathway inhibitor. This study describes a robust method to generate chondrocytes from hiMPCs with low hypertrophy for hyaline cartilage repair, as well as elucidates the difference between hMSCs and hiMPCs in response to TGFβ. Our results also indicated the importance of activating both Smad2/3 and Smad1/5 in the initiation of chondrogenesis. Activation of Smad1/5 is critical in initiating chondrogenesis of multipotent progenitor cells (iMPCs) created from human induced pluripotent stem cells (iPSCs). iMPCs display rapidly decreased cartilage‐forming capacity with the increase of passage number. When subjected to pellet culture in the medium supplemented with TGFβ3 and BMP6, iMPCs can generate hyaline‐like cartilage with minimal chondrocytic hypertrophy phenotype.
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影响因子：
5.8
作者：
Gu, Zuguang;Eils, Roland;Schlesner, Matthias
通讯作者：
Schlesner, Matthias
影响因子：
5.5
作者：
Kreuser U;Buchert J;Haase A;Richter W;Diederichs S
通讯作者：
Diederichs S
CD105通过Smad2信号促进滑膜来源的间充质干细胞的软骨形成
DOI：
10.1016/j.bbrc.2016.04.101
发表时间：
2016-05-27
影响因子：
3.1
作者：
Fan, Wenshuai;Li, Jinghuan;Yan, Zuoqin
通讯作者：
Yan, Zuoqin
影响因子：
5.6
作者：
Afzal, F;Pratap, J;Javed, A
通讯作者：
Javed, A
DOI：
10.1007/978-1-4939-7799-4_4
发表时间：
2018-01-01
期刊：
ADIPOSE-DERIVED STEM CELLS: METHODS AND PROTOCOLS, 2ND EDITION
影响因子：
--
作者：
Hafner, Anne-Laure;Mohsen-Kanson, Tala;Dani, Christian
通讯作者：
Dani, Christian