Transient receptor potential vanilloid 4 as a regulator of induced pluripotent stem cell chondrogenesis,STEM CELLS

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Transient receptor potential vanilloid 4 as a regulator of induced pluripotent stem cell chondrogenesis
STEM CELLS ( IF 4.0 ) Pub Date : 2021-08-24 , DOI: 10.1002/stem.3440
Vincent P Willard ₁ , Holly A Leddy ₂ , Daniel Palmer _{3,

4,

5} , Chia-Lung Wu _{3,

4,

5,

6} , Wolfgang Liedtke ₇ , Farshid Guilak _{1,

3,

4,

5}

Affiliation

Transient receptor potential vanilloid 4 (TRPV4) is a polymodal calcium-permeable cation channel that is highly expressed in cartilage and is sensitive to a variety of extracellular stimuli. The expression of this channel has been associated with the process of chondrogenesis in adult stem cells as well as several cell lines. Here, we used a chondrogenic reporter (Col2a1-GFP) in murine induced pluripotent stem cells (iPSCs) to examine the hypothesis that TRPV4 serves as both a marker and a regulator of chondrogenesis. Over 21 days of chondrogenesis, iPSCs showed significant increases in Trpv4 expression along with the standard chondrogenic gene markers Sox9, Acan, and Col2a1, particularly in the green fluorescent protein positive (GFP+) chondroprogenitor subpopulation. Increased gene expression for Trpv4 was also reflected by the presence of TRPV4 protein and functional Ca²⁺ signaling. Daily activation of TRPV4 using the specific agonist GSK1016790A resulted in significant increases in cartilaginous matrix production. An improved understanding of the role of TRPV4 in chondrogenesis may provide new insights into the development of new therapeutic approaches for diseases of cartilage, such as osteoarthritis, or channelopathies and hereditary disorders that affect cartilage during development. Harnessing the role of TRPV4 in chondrogenesis may also provide a novel approach for accelerating stem cell differentiation in functional tissue engineering of cartilage replacements for joint repair.

中文翻译：

瞬时受体电位香草素 4 作为诱导多能干细胞软骨形成的调节剂

瞬时受体电位香草酸 4 (TRPV4) 是一种多峰钙渗透性阳离子通道，在软骨中高度表达，对多种细胞外刺激敏感。该通道的表达与成体干细胞以及几种细胞系中的软骨形成过程有关。在这里，我们在小鼠诱导的多能干细胞 (iPSCs) 中使用软骨形成报告基因 ( Col2a1-GFP ) 来检验 TRPV4 作为软骨形成的标记物和调节剂的假设。在 21 天的软骨形成过程中，iPSC与标准的软骨形成基因标记Sox9、Acan和Col2a1一起显示Trpv4表达显着增加, 特别是在绿色荧光蛋白阳性 (GFP+) 软骨祖细胞亚群中。Trpv4基因表达的增加也反映在 TRPV4 蛋白和功能性 Ca ^{2+的存在上}发信号。使用特异性激动剂 GSK1016790A 每天激活 TRPV4 导致软骨基质产量显着增加。对 TRPV4 在软骨形成中作用的更好理解可能为开发新的软骨疾病治疗方法提供新的见解，例如骨关节炎，或在发育过程中影响软骨的通道病和遗传性疾病。利用 TRPV4 在软骨形成中的作用还可以提供一种新方法，用于加速干细胞分化在用于关节修复的软骨替代物的功能性组织工程中。

更新日期：2021-08-24

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