Niche-mediated BMP/SMAD signaling regulates lung alveolar stem cell proliferation and differentiation.
Niche-mediated BMP/SMAD signaling regulates lung alveolar stem cell proliferation and differentiation.
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DOI：
10.1242/dev.163014
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发表时间：
2018-05-11
期刊：
影响因子：
--
通讯作者：
Hogan BLM
中科院分区：
文献类型：
--
作者：
Chung MI;Bujnis M;Barkauskas CE;Kobayashi Y;Hogan BLM
骨形态发生蛋白（BMP）信号通路，包括其拮抗剂，在肺发育以及基底干细胞的气管上皮再生中发挥作用。在此，我们探究其在肺泡区域的作用，其中2型上皮细胞（AT2s）和血小板衍生生长因子受体α阳性的2型相关基质细胞（TASCs）是干细胞微环境的组成部分。我们利用类器官以及肺切除术后（PNX）体内肺泡的再生长——这一过程需要AT2s增殖并分化为1型细胞（AT1s）。BMP信号在AT2s和TASCs中是活跃的，在PNX后与拮抗剂上调相关而短暂下降，并在AT2s向AT1s分化过程中恢复。在类器官中，BMP4抑制AT2增殖，而拮抗剂（卵泡抑素、头蛋白）以分化为代价促进AT2自我更新。功能获得和功能缺失的基因操作表明，PNX后AT2s中BMP信号降低允许自我更新但减少分化；相反，BMP信号增加促进AT1形成。在血小板衍生生长因子受体α阳性细胞中持续的BMP信号在PNX后以及类器官培养中均降低其对AT2的支持功能。我们的数据揭示了BMP信号在肺泡再生过程中的多种细胞类型特异性作用。
总结：利用肺泡类器官以及肺切除术后体内肺泡再生长的研究确定了BMP信号在调节成年肺泡再生中许多动态的和细胞类型特异性的作用。
The bone morphogenetic protein (BMP) signaling pathway, including antagonists, functions in lung development and regeneration of tracheal epithelium from basal stem cells. Here, we explore its role in the alveolar region, where type 2 epithelial cells (AT2s) and Pdgfrα+ type 2-associated stromal cells (TASCs) are components of the stem cell niche. We use organoids and in vivo alveolar regrowth after pneumonectomy (PNX) – a process that requires proliferation of AT2s and differentiation into type 1 cells (AT1s). BMP signaling is active in AT2s and TASCs, transiently declines post-PNX in association with upregulation of antagonists, and is restored during differentiation of AT2s to AT1s. In organoids, BMP4 inhibits AT2 proliferation, whereas antagonists (follistatin, noggin) promote AT2 self-renewal at the expense of differentiation. Gain- and loss-of-function genetic manipulation reveals that reduced BMP signaling in AT2s after PNX allows self-renewal but reduces differentiation; conversely, increased BMP signaling promotes AT1 formation. Constitutive BMP signaling in Pdgfrα+ cells reduces their AT2 support function, both after PNX and in organoid culture. Our data reveal multiple cell-type-specific roles for BMP signaling during alveolar regeneration. Summary: Studies using alveolar organoids and in vivo alveolar regrowth post-pneumonectomy establish many dynamic and cell-type-specific roles for BMP signaling in regulating adult alveolar regeneration.
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影响因子：
23.9
作者：
Lechner AJ;Driver IH;Lee J;Conroy CM;Nagle A;Locksley RM;Rock JR
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DOI：
10.1165/rcmb.2012-0030oc
发表时间：
2012-10-01
影响因子：
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作者：
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通讯作者：
Perl, Anne-Karina T.
影响因子：
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作者：
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通讯作者：
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