A stem cell-driven lymphoangiogenic switch

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. Blood endothelial cells and lymphatic endothelial cells in the mouse back skin at the first telogen were FACS-purified for RNA-seq analysis.组织依赖干细胞（Stem Cells, SCs）维持机体稳态并完成创伤修复。干细胞定居于特化微环境（niche，即干细胞龛）中，其复杂性及在调控组织生长中的作用仍有待逐步阐明。本研究证实毛细淋巴管为关键的干细胞龛组分。在皮肤组织中，当每个毛囊（Hair Follicle, HF）的干细胞处于非再生阶段时，淋巴管会在其周围形成紧密网络，并在毛囊再生时发生重塑。为探究其背后机制，我们解析了调控淋巴管行为的干细胞分泌组转换现象。静息状态的干细胞表达血管生成素样7（Angiopoietin-like 7, Angptl7），以促进淋巴引流。而在被激活后，干细胞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：无论是清除淋巴管、沉默Angptl7基因，还是过度激活抗淋巴管生成程序，都会导致干细胞提前增殖，且毛囊再生过程变得异步。本研究揭示了此前未被充分认知的毛细淋巴管作为干细胞龛组分的新角色，并阐明了干细胞如何在整个组织范围内协调自身活性。我们对小鼠背部皮肤处于首个毛囊休止期（telogen）的血管内皮细胞与淋巴管内皮细胞进行了荧光激活细胞分选纯化（Fluorescence-Activated Cell Sorting, FACS），以开展RNA测序（RNA Sequencing, RNA-seq）分析。