A stem cell-driven lymphoangiogenic switch coordinates tissue regeneration

Tissues rely on stem cells (SCs) for homeostasis and wound-repair. SCs reside in specialized microenvironments (niches) whose complexities and roles in orchestrating tissue growth are still unfolding. Here, we identify lymphatic capillaries as critical SC niche components. In skin, lymphatics form intimate networks around the SCs of each hair follicle (HF) during their non-regenerative phase, and remodel upon regeneration. Seeking understanding, we unravel a secretome switch within SCs that controls lymphatic behavior. Resting SCs express Angiopoietin-like 7 (Angptl7), promoting lymphatic drainage. Upon activation, SCs trigger an anti-lympho-angiogenic program, transiently sparking lymphatic dilation and dampened drainage. In mammals, this dynamic aria between SCs and lymphatics is essential for coordinating HFSC behavior and hair regeneration: Upon either depleting lymphatics, silencing Angptl7 or super-activating anti-lympho-angiogenesis, SCs precociously proliferate and HF regeneration becomes asynchronous. In unearthing lymphatic capillaries as a hitherto under-appreciated SC-niche element, we've learned how SCs coordinate their activity across a tissue. Mouse hair follicle stem cells were purified from Krt14-H2BGFP mice along the hair cycle. The sorted cells were analyzed by RNAseeq.组织依赖干细胞（stem cells，SCs）维持机体稳态与创伤修复。干细胞定位于特化的微环境（即干细胞龛，niche）中，其复杂性及在调控组织生长中的作用仍有待进一步阐明。本研究证实毛细淋巴管（lymphatic capillaries）是干细胞龛的关键组成部分。在皮肤组织中，毛细淋巴管会在毛囊（hair follicle，HF）干细胞处于非再生阶段时，于其周围形成紧密的网络结构，并在毛囊再生过程中发生重塑。为解析这一现象的机制，我们揭示了干细胞内一类调控淋巴管行为的分泌组（secretome）转换程序。静息状态的干细胞表达血管生成素样7（Angiopoietin-like 7，Angptl7），以此促进淋巴引流。而当干细胞被激活后，其会启动抗淋巴管生成程序，短暂引发淋巴管扩张并削弱淋巴引流功能。在哺乳动物体内，干细胞与淋巴管之间的这种动态互作对于协调毛囊干细胞（hair follicle stem cells，HFSC）的行为与毛发再生至关重要：若通过清除毛细淋巴管、沉默Angptl7基因或过度激活抗淋巴管生成程序，干细胞会提前增殖，且毛囊再生将变得不同步。本研究明确了毛细淋巴管这一此前未被充分认知的干细胞龛组分，并揭示了干细胞如何协调其在整个组织中的活性。研究人员沿毛发周期从Krt14-H2BGFP转基因小鼠中分离纯化了小鼠毛囊干细胞，并通过RNA测序（RNA-seq）对分选得到的细胞进行了分析。