Cross-linked matrix rigidity and soluble retinoids synergize in nuclear lamina regulation of stem cell differentiation.
Cross-linked matrix rigidity and soluble retinoids synergize in nuclear lamina regulation of stem cell differentiation.
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DOI：
10.1091/mbc.e17-01-0010
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发表时间：
2017-07-07
影响因子：
3.3
通讯作者：
Discher DE
中科院分区：
文献类型：
--
作者：
Ivanovska IL;Swift J;Spinler K;Dingal D;Cho S;Discher DE
交联胶原蛋白-I的纳米膜相当于相对坚硬的基质，其使细胞核变硬，与层粘连蛋白-A（包括突变体早老蛋白）、视黄酸转录因子水平和活性以及骨诱导广泛相关。体外结果得到体内异位骨形成研究的支持。来自细胞外基质和可溶性因子的协同信号在分化中常常是模糊的。在这里，交联胶原的刚性与类维生素A在人骨髓间充质干细胞（MSC）的成骨中协同作用。胶原纳米膜作为模型基质，MSC可以很容易地变形，除非膜是酶促交联的，这促进了细胞的扩散和细胞核的硬化，因为肌动球蛋白组装和核骨架层蛋白A增加。已知层粘连蛋白A的表达受视黄酸受体（RAR）转录因子控制，但软基质阻止对任何类视黄酸的任何反应。需要刚性基质来诱导RARG同种型的快速核积累，并且RARG特异性拮抗剂增加或维持层粘连蛋白-A的表达，以及RARG激动剂抑制表达。层粘连蛋白-A的早老蛋白等位基因在iPSC衍生的MSC中以相同的方式调节。成骨标志物的最终表达还需要刚性基质，RARG拮抗剂强烈驱动刚性基质上的层粘连蛋白A依赖性成骨，预处理的异种移植物在体内钙化至与天然骨相似的程度。蛋白质组学检测的机械敏感性层蛋白-A和类维生素A的目标强调了分化中不溶性和可溶性线索的收敛协同作用。
A nanofilm of cross-linked collagen-I is equivalent to a relatively stiff matrix, which stiffens the nucleus, correlating broadly with lamin-A (including mutant progerin), retinoic acid transcription factor level and activity, and osteoinduction. In vitro results are supported by studies of ectopic bone formation in vivo. Synergistic cues from extracellular matrix and soluble factors are often obscure in differentiation. Here the rigidity of cross-linked collagen synergizes with retinoids in the osteogenesis of human marrow mesenchymal stem cells (MSCs). Collagen nanofilms serve as a model matrix that MSCs can easily deform unless the film is enzymatically cross-linked, which promotes the spreading of cells and the stiffening of nuclei as both actomyosin assembly and nucleoskeletal lamin-A increase. Expression of lamin-A is known to be controlled by retinoic acid receptor (RAR) transcription factors, but soft matrix prevents any response to any retinoids. Rigid matrix is needed to induce rapid nuclear accumulation of the RARG isoform and for RARG-specific antagonist to increase or maintain expression of lamin-A as well as for RARG-agonist to repress expression. A progerin allele of lamin-A is regulated in the same manner in iPSC-derived MSCs. Rigid matrices are further required for eventual expression of osteogenic markers, and RARG-antagonist strongly drives lamin-A–dependent osteogenesis on rigid substrates, with pretreated xenografts calcifying in vivo to a similar extent as native bone. Proteomics-detected targets of mechanosensitive lamin-A and retinoids underscore the convergent synergy of insoluble and soluble cues in differentiation.