Early forming label-retaining muscle stem cells require p27kip1 for maintenance of the primitive state.
Early forming label-retaining muscle stem cells require p27kip1 for maintenance of the primitive state.
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DOI：
10.1242/dev.100842
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发表时间：
2014-04
期刊：
影响因子：
--
通讯作者：
Brack AS
中科院分区：
文献类型：
--
作者：
Chakkalakal JV;Christensen J;Xiang W;Tierney MT;Boscolo FS;Sacco A;Brack AS
在不同的小生境中，高功能干细胞的子集保持在相对休眠而不是增殖状态。我们对组织更新增加条件下组织特异性干细胞增殖动力学的理解仍然有限。使用TetO-H2 B-GFP报告增殖历史，我们确定骨骼肌干细胞，或卫星细胞，保留（LRC）或失去（nonLRC）的H2 B-GFP标记。我们在小鼠中发现，LRC和nonLRC在出生时形成，并在出生后的生长和成年肌肉修复过程中持续存在。在功能上，LRC和nonLRC出生时是等同的，并在出生后成熟过程中过渡到不同的和分层组织的子集。成年LRC产生LRC和nonLRC;前者能够自我更新，而后者仅限于分化。表达分析显示CIP/KIP家族成员p21 cip 1（Cdkn 1a）和p27 kip 1（Cdkn 1b）在LRC中以较高水平表达。根据LRC命运中的关键作用，p27 kip 1的缺失促进了体外LRC的增殖和分化，并损害了肌肉损伤后卫星细胞的自我更新。相比之下，p21 cip 1的损失只影响nonLRC，其中肌源性承诺被抑制。我们的研究结果提供的证据表明，自我更新潜力的限制LRC建立在生命早期，并通过细胞周期抑制剂p27 kip 1在增加组织周转期间维持。它们还揭示了CIP/KIP家族成员在干细胞层次结构中的离散步骤中的差异作用。
Across different niches, subsets of highly functional stem cells are maintained in a relatively dormant rather than proliferative state. Our understanding of proliferative dynamics in tissue-specific stem cells during conditions of increased tissue turnover remains limited. Using a TetO-H2B-GFP reporter of proliferative history, we identify skeletal muscle stem cell, or satellite cells, that retain (LRC) or lose (nonLRC) the H2B-GFP label. We show in mice that LRCs and nonLRCs are formed at birth and persist during postnatal growth and adult muscle repair. Functionally, LRCs and nonLRCs are born equivalent and transition during postnatal maturation into distinct and hierarchically organized subsets. Adult LRCs give rise to LRCs and nonLRCs; the former are able to self-renew, whereas the latter are restricted to differentiation. Expression analysis revealed the CIP/KIP family members p21cip1 (Cdkn1a) and p27kip1 (Cdkn1b) to be expressed at higher levels in LRCs. In accordance with a crucial role in LRC fate, loss of p27kip1 promoted proliferation and differentiation of LRCs in vitro and impaired satellite cell self-renewal after muscle injury. By contrast, loss of p21cip1 only affected nonLRCs, in which myogenic commitment was inhibited. Our results provide evidence that restriction of self-renewal potential to LRCs is established early in life and is maintained during increased tissue turnover through the cell cycle inhibitor p27kip1. They also reveal the differential role of CIP/KIP family members at discrete steps within the stem cell hierarchy.
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影响因子：
2.7
作者：
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影响因子：
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作者：
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