Two-step generation of mesenchymal stem/stromal cells from human pluripotent stem cells with reinforced efficacy upon osteoarthritis rabbits by HA hydrogel.
Two-step generation of mesenchymal stem/stromal cells from human pluripotent stem cells with reinforced efficacy upon osteoarthritis rabbits by HA hydrogel.
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从人多能干细胞中两步生成间充质干细胞/基质细胞，通过 HA 水凝胶增强对骨关节炎兔的功效
DOI：
10.1186/s13578-020-00516-x
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发表时间：
2021-01-06
影响因子：
7.5
通讯作者：
Li Z
中科院分区：
文献类型：
--
作者：
Zhang L;Wei Y;Chi Y;Liu D;Yang S;Han Z;Li Z
目前的研究已经照亮了人多能干细胞（hPSC）来源的间充质干/基质细胞（MSCs）在再生医学中的美好前景。然而，其签名和替代生物材料在骨关节炎（OA）中的应用的系统研究仍然不清楚。在此，我们最初利用小分子文库介导的编程策略用于hPSC-MSC诱导。通过流式细胞术、细胞活力、有核细胞计数、伤口愈合和微管形成实验以及与T淋巴细胞共培养等多方面的分析，系统评价了hPSC-MSCs与HA水凝胶复合物的体外特征和体内治疗兔骨关节炎模型的疗效。我们发现，LLY-507和AZD 5153的组合足以从具有干细胞的hESC和hiPSC（POU5F1/SOX 2/NANOG）高效诱导CD73 + CD90 + CD105 + CD31 − CD34 − CD45 − HLA-DR − MSC。程序化的hPSC-MSCs显示保守的转录组变异，经历了一个异质的中间阶段，表达间质相关基因（NT5E，ENG，VIM和FN 1），并显示出典型的细胞形态学，免疫表型和正常的核型，多谱系分化潜力，良好的细胞活力，促血管生成和免疫调节特性。同时，该细胞群在体内对HA水凝胶治疗的兔OA具有较好的修复和改善作用。总的来说，我们建立了一个快速和方便的程序hPSC-MSC生成没有冗余的操作。将取之不尽的hPSC-MSCs与优良的生物材料相结合，将极大地促进骨关节炎（OA）治疗的基础和临床研究。
Current studies have enlightened the rosy prospects of human pluripotent stem cell (hPSC)-derived mesenchymal stem/stromal cells (MSCs) in regenerative medicine. However, systematic investigation of their signatures and applications with alternative biomaterials in osteoarthritis (OA) remains indistinct. Herein, we initially took advantage of a small molecule library-mediated programming strategy for hPSC-MSC induction. Then, with the aid of multifaceted analyses such as flow cytometry (FCM), chromosome karyocyte and cell vitality, wound healing and microtubule formation assay and coculturing with T lymphocytes, we systematically evaluated the characterizations of signatures in vitro and the in vivo efficacy of hPSC-MSCs and HA hydrogel composite on rabbit osteoarthritis model. We found the combination of LLY-507 and AZD5153 was sufficient for high-efficiency CD73+CD90+CD105+CD31−CD34−CD45−HLA-DR− MSC induction from both hESCs and hiPSCs with stemness (POU5F1/SOX2/NANOG). The programmed hPSC-MSCs revealed conservative transcriptome variations and went through a heterogeneous intermediate-stage with mesenchymal-associated gene expression (NT5E, ENG, VIM and FN1) as well as displayed typical cytomorphology, immunophenotypes and normal karyotyping, multilineage differentiation potential, favorable cell vitality, proangiogenic and immunoregulatory properties in vitro. Meanwhile, the cell population exhibited preferable restorative and ameliorative function on OA rabbits with HA hydrogel in vivo. Collectively, we established a rapid and convenient procedure for hPSC-MSC generation without redundant manipulations. The fundamental and clinical studies upon osteoarthritis (OA) treatment would benefit tremendously from the combination of the inexhaustible hPSC-MSCs and advantageous biomaterials.
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