Osteoblast de- and redifferentiation are controlled by a dynamic response to retinoic acid during zebrafish fin regeneration
Osteoblast de- and redifferentiation are controlled by a dynamic response to retinoic acid during zebrafish fin regeneration
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DOI：
10.1242/dev.120204
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发表时间：
2015-09-01
期刊：
影响因子：
4.6
通讯作者：
Begemann, Gerrit
中科院分区：
文献类型：
--
作者：
Blum, Nicola;Begemann, Gerrit
斑马鱼通过形成特定于组织的胚泡细胞来修复被切断的鳍，这些细胞可以协调地再生丢失的结构。FIN截断触发了再生所需的几个可扩散信号因子的合成，提出了如何保护细胞谱系特定的程序免受邻近FIN组织之间的再生串扰的问题。在鳍再生期间，成骨细胞从非循环的成熟状态恢复到循环的成骨前状态，以在胚泡内建立祖细胞池。经过几轮增殖后，前成骨细胞重新分化，产生新骨。胚泡的形成和增殖是由维甲酸(RA)的持续合成驱动的。在这里，我们发现成骨细胞的去分化和再分化受到RA信号的抑制，我们揭示了骨再生计划是如何在大量RA合成的背景下实现的。残端成骨细胞通过上调RA降解酶cyp26b1的表达来促进胚泡形成。再分化是由RA的一个假定的梯度控制的，在这个过程中，胚泡末端高水平的RA抑制了再分化。我们表明，这可能是通过抑制BMP信号和促进Wnt/β-catenin信号的机制实现的。反过来，cyp26b1(+)成纤维细胞来源的胚芽细胞在更近端的再生中作为一个汇，降低RA水平，从而允许邻近的前成骨细胞分化。我们的发现揭示了一种机制，解释了成骨细胞再生计划如何被保护，使其免受与邻近成纤维细胞的不利串扰，从而促进了我们对RA对骨修复调控的理解。
Zebrafish restore amputated fins by forming tissue-specific blastema cells that coordinately regenerate the lost structures. Fin amputation triggers the synthesis of several diffusible signaling factors that are required for regeneration, raising the question of how cell lineage-specific programs are protected from regenerative crosstalk between neighboring fin tissues. During fin regeneration, osteoblasts revert from a non-cycling, mature state to a cycling, preosteoblastic state to establish a pool of progenitors within the blastema. After several rounds of proliferation, preosteoblasts redifferentiate to produce new bone. Blastema formation and proliferation are driven by the continued synthesis of retinoic acid (RA). Here, we find that osteoblast dedifferentiation and redifferentiation are inhibited by RA signaling, and we uncover how the bone regenerative program is achieved against a background of massive RA synthesis. Stump osteoblasts manage to contribute to the blastema by upregulating expression of the RA-degrading enzyme cyp26b1. Redifferentiation is controlled by a presumptive gradient of RA, in which high RA levels towards the distal tip of the blastema suppress redifferentiation. We show that this might be achieved through a mechanism involving repression of Bmp signaling and promotion of Wnt/beta-catenin signaling. In turn, cyp26b1(+) fibroblast-derived blastema cells in the more proximal regenerate serve as a sink to reduce RA levels, thereby allowing differentiation of neighboring preosteoblasts. Our findings reveal a mechanism explaining how the osteoblast regenerative program is protected from adverse crosstalk with neighboring fibroblasts that advances our understanding of the regulation of bone repair by RA.