Effect of a retinoic acid analogue on BMP-driven pluripotent stem cell chondrogenesis
Effect of a retinoic acid analogue on BMP-driven pluripotent stem cell chondrogenesis
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DOI：
10.1101/2023.06.20.545738
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发表时间：
2023-06
期刊：
影响因子：
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通讯作者：
F. Mancini;Paul A Humphreys;Steven Woods;N. Bates;Sara Cuvertino;Julieta O’Flaherty;Leela C. Biant;M. Domingos;S. Kimber
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文献类型：
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作者：
F. Mancini;Paul A Humphreys;Steven Woods;N. Bates;Sara Cuvertino;Julieta O’Flaherty;Leela C. Biant;M. Domingos;S. Kimber
骨关节炎是最常见的退行性关节疾病，导致关节软骨（AC）退化，慢性疼痛和不动。缺乏提供组织修复的适当疗法，加上关节置换植入物的寿命有限，表明需要替代AC再生策略。人多能干细胞（hPSC）分化成AC祖细胞可以提供长期再生解决方案，但由于持续依赖生长因子来重现发育信号传导过程，因此仍然受到限制。最近，TTNPB，视黄酸受体（RAR）的小分子激活剂，已被证明足以指导hPSC的中胚层特化和早期软骨形成。在这里，我们修改了我们以前的分化方案，通过用TTNPB补充细胞并在特定时间施用BMP 2来增强早期发育。转录组学分析表明，RAR信号的激活显着上调与肢体和胚胎骨骼发育相关的基因在早期阶段的协议和上调与AC发展在后期阶段的基因。从RAPID-E获得的软骨祖细胞可以产生表达AC相关基质蛋白（如Lubricin、聚集蛋白聚糖和胶原蛋白II）的软骨颗粒。该方案可以为骨关节炎的细胞治疗策略奠定基础，并提高对人类AC发展的理解。
Osteoarthritis is the most common degenerative joint condition, leading to articular cartilage (AC) degradation, chronic pain and immobility. The lack of appropriate therapies that provide tissue restoration combined with the limited lifespan of joint-replacement implants indicate the need for alternative AC regeneration strategies. Differentiation of human pluripotent stem cells (hPSCs) into AC progenitors may provide a long-term regenerative solution but are still limited due to the continued reliance upon growth factors to recapitulate developmental signalling processes. Recently, TTNPB, a small molecule activator of retinoic acid receptors (RARs), has been shown to be sufficient to guide mesodermal specification and early chondrogenesis of hPSCs. Here, we modified our previous differentiation protocol, by supplementing cells with TTNPB and administering BMP2 at specific times to enhance early development. Transcriptomic analyses indicated that activation of RAR signalling significantly upregulated genes related to limb and embryonic skeletal development in the early stages of the protocol and upregulated genes related to AC development in later stages. Chondroprogenitors obtained from RAPID-E could generate cartilaginous pellets that expressed AC-related matrix proteins such as Lubricin, Aggrecan, and Collagen II. This protocol could lay the foundations for cell therapy strategies for osteoarthritis and improve the understanding of AC development in humans.