Smad1 and 5 but not Smad8 establish stem cell quiescence which is critical to transform the premature hair follicle during morphogenesis toward the postnatal state.
Smad1 and 5 but not Smad8 establish stem cell quiescence which is critical to transform the premature hair follicle during morphogenesis toward the postnatal state.
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DOI：
10.1002/stem.1548
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发表时间：
2014-02
期刊：
影响因子：
5.2
通讯作者：
Kobielak, Krzysztof
中科院分区：
文献类型：
--
作者：
Kandyba, Eve;Hazen, Virginia M.;Kobielak, Agnieszka;Butler, Samantha J.;Kobielak, Krzysztof
毛囊（HFs）是一种可再生的微型器官，为研究毛囊干细胞（hfSCs）稳态和分化的调控机制提供了一个高信息量的模型系统。骨形态发生蛋白（Bone Morphogenetic Protein， BMP）信号在这两个过程中都起着关键作用，控制着hfSCs在基质祖细胞膨胀和分化过程中的静止。然而，BMP信号的规范或非规范途径是否负责这些过程仍未解决。本研究中，我们在小鼠皮肤毛发形态发生和出生后循环过程中，有条件地切除了BMP信号的两个典型效应物Smad1和Smad5。在形态发生过程中，表皮中Smad1和Smad5 （dKO）的缺失导致新生儿死亡，缺乏可见的胡须。有趣的是，磷酸化smads （pSmads）的激活模式不同，pSmad8仅限于表皮，pSmad1和pSmad5仅在HFs中激活。植入dKO皮肤后发现毛发形态发生迟缓，不能分化为可见毛发。在长时间生长的dKO HFs中，静止的hfSCs无法形成隆起前和隆起库。令人惊讶的是，在出生后休止期HFs中，pSmad8的表达不再局限于表皮，也存在于dKO凸起的hfSCs和基质祖细胞中。虽然pSmad8活性单独不能阻止dKO hfSCs的早生原激活，但它能维持有效的产后分化和可见毛发再生。总之，我们的数据表明pSmad8与pSmad1和pSmad5在hfSCs调节和毛发形态发生中具有独特的非重叠功能，但在成人毛祖细胞分化中具有冗余作用，在典型BMP信号传导中发挥关键作用。
Hair follicles (HFs) are regenerative mini-organs that offer a highly informative model system to study the regulatory mechanisms of hair follicle stem cells (hfSCs) homeostasis and differentiation. Bone Morphogenetic Protein (BMP) signaling is key in both of these processes, governing hfSCs quiescence in the bulge and differentiation of matrix progenitors. However, whether canonical or non-canonical pathways of BMP signaling are responsible for these processes remains unresolved. Here, we conditionally ablated two canonical effectors of BMP signaling, Smad1 and Smad5 during hair morphogenesis and postnatal cycling in mouse skin. Deletion of Smad1 and Smad5 (dKO) in the epidermis during morphogenesis resulted in neonatal lethality with lack of visible whiskers. Interestingly, distinct patterns of phospho-Smads (pSmads) activation were detected with pSmad8 restricted to epidermis and pSmad1 and pSmad5 exclusively activated in HFs. Engraftment of dKO skin revealed retarded hair morphogenesis and failure to differentiate into visible hair. The formation of the pre-bulge and bulge reservoir for quiescent hfSCs was precluded in dKO HFs which remained in prolonged anagen. Surprisingly, in postnatal telogen HFs, pSmad8 expression was no longer limited to epidermis and was also present in dKO bulge hfSCs and matrix progenitors. Although pSmad8 activity alone could not prevent dKO hfSCs precocious anagen activation it sustained efficient postnatal differentiation and regeneration of visible hairs. Together, our data suggest a pivotal role for canonical BMP signaling demonstrating distinguished non-overlapping function of pSmad8 with pSmad1 and pSmad5 in hfSCs regulation and hair morphogenesis but a redundant role in adult hair progenitors differentiation.
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影响因子：
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