Department of Biomedicine, University Hospital Basel, Basel, Switzerland.
University of Basel, Basel, Switzerland.
J Am Heart Assoc. 2017 Oct 24;6(10):e005920. doi: 10.1161/JAHA.117.005920.
Recent studies suggest that adult cardiac progenitor cells (CPCs) can produce new cardiac cells. Such cell formation requires an intricate coordination of progenitor cell proliferation and commitment, but the molecular cues responsible for this regulation in CPCs are ill defined.
Extracellular matrix components are important instructors of cell fate. Using laminin and fibronectin, we induced two slightly distinct CPC phenotypes differing in proliferation rate and commitment status and analyzed the early transcriptomic response to CPC adhesion (<2 hours). Ninety-four genes were differentially regulated on laminin versus fibronectin, consisting of mostly downregulated genes that were enriched for Yes-associated protein (YAP) conserved signature and TEA domain family member 1 (TEAD1)-related genes. This early gene regulation was preceded by the rapid cytosolic sequestration and degradation of YAP on laminin. Among the most strongly regulated genes was polo-like kinase 2 (). expression depended on YAP stability and was enhanced in CPCs transfected with a nuclear-targeted mutant YAP. Phenotypically, the early downregulation of on laminin was succeeded by lower cell proliferation, enhanced lineage gene expression (24 hours), and facilitated differentiation (3 weeks) compared with fibronectin. Finally, overexpression of Plk2 enhanced CPC proliferation and knockdown of Plk2 induced the expression of lineage genes.
Plk2 acts as coordinator of cell proliferation and early lineage commitment in CPCs. The rapid downregulation of Plk2 on YAP inactivation marks a switch towards enhanced commitment and facilitated differentiation. These findings link early gene regulation to cell fate and provide novel insights into how CPC proliferation and differentiation are orchestrated.
最近的研究表明，成人心脏祖细胞（CPCs）可以产生新的心肌细胞。这种细胞的形成需要祖细胞增殖和分化的精细协调，但负责 CPC 中这种调节的分子线索还不清楚。
细胞外基质成分是细胞命运的重要指导者。我们使用层粘连蛋白和纤维连接蛋白诱导了两种略有不同的 CPC 表型，其增殖率和分化状态不同，并分析了 CPC 黏附后（<2 小时）早期转录组的反应。94 个基因在层粘连蛋白与纤维连接蛋白上的表达存在差异，主要是下调基因，这些基因富集了 Yes 相关蛋白（YAP）保守基序和 TEA 结构域家族成员 1（TEAD1）相关基因。这种早期基因调控之前，YAP 在层粘连蛋白上迅速发生细胞质隔离和降解。在受调控最强的基因中，有 polo 样激酶 2（Plk2）。Plk2 表达依赖于 YAP 的稳定性，在转染核靶向突变 YAP 的 CPC 中表达增强。表型上，与纤维连接蛋白相比，Plk2 在层粘连蛋白上的早期下调伴随着细胞增殖降低、增强的谱系基因表达（24 小时）和促进分化（3 周）。最后，Plk2 的过表达增强了 CPC 的增殖，而 Plk2 的敲低诱导了谱系基因的表达。
Plk2 作为 CPC 中细胞增殖和早期谱系分化的协调者。Plk2 在 YAP 失活后迅速下调标志着向增强的分化和促进分化的转变。这些发现将早期基因调控与细胞命运联系起来，为 CPC 增殖和分化的协调提供了新的见解。
