Characterization in mice of the resident mesenchymal niche maintaining AT2 stem cell proliferation in homeostasis and disease,STEM CELLS

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Characterization in mice of the resident mesenchymal niche maintaining AT2 stem cell proliferation in homeostasis and disease
STEM CELLS ( IF 4.0 ) Pub Date : 2021-05-28 , DOI: 10.1002/stem.3423
Sara Taghizadeh _{1,

2} , Monika Heiner ₂ , Ana Ivonne Vazquez-Armendariz ₃ , Jochen Wilhelm _{2,

3} , Susanne Herold ₂ , Chengshui Chen ₁ , Jin San Zhang ₁ , Saverio Bellusci _{1,

2}

Affiliation

Resident mesenchymal cells (rMCs defined as Cd31^NegCd45^NegEpcam^Neg) control the proliferation and differentiation of alveolar epithelial type 2 (AT2) stem cells in vitro. The identity of these rMCs is still elusive. Among them, Axin2^Pos mesenchymal alveolar niche cells (MANCs), which are expressing Fgf7, have been previously described. We propose that an additional population of rMCs, expressing Fgf10 (called rMC-Sca1^PosFgf10^Pos) are equally important to maintain AT2 stem cell proliferation. The alveolosphere model, based on the AT2-rMC co-culture in growth factor-reduced Matrigel, was used to test the efficiency of different rMC subpopulations isolated by FACS from adult murine lung to sustain the proliferation and differentiation of AT2 stem cells. We demonstrate that rMC-Sca1^PosFgf10^Pos cells are efficient to promote the proliferation and differentiation of AT2 stem cells. Co-staining of adult lung for Fgf10 mRNA and Sftpc protein respectively, indicate that 28% of Fgf10^Pos cells are located close to AT2 cells. Co-ISH for Fgf7 and Fgf10 indicate that these two populations do not significantly overlap. Gene arrays comparing rMC-Sca1^PosAxin2^Pos and rMC-Sca1^PosFgf10^Pos support that these two cell subsets express differential markers. In addition, rMC function is decreased in obese ob/ob mutant compared to WT mice with a much stronger loss of function in males compared to females. In conclusion, rMC-Sca1^PosFgf10^Pos cells play important role in supporting AT2 stem cells proliferation and differentiation. This result sheds a new light on the subpopulations of rMCs contributing to the AT2 stem cell niche in homeostasis and in the context of pre-existing metabolic diseases.

中文翻译：

在稳态和疾病中维持 AT2 干细胞增殖的常驻间充质生态位的小鼠特征

驻留间充质细胞（rMC 定义为 Cd31 ^Neg Cd45 ^Neg Epcam ^Neg）在体外控制肺泡上皮 2 型 (AT2) 干细胞的增殖和分化。这些 rMC 的身份仍然难以捉摸。其中，先前已经描述了表达Fgf7的 Axin2 ^Pos间充质肺泡小生境细胞 (MANC) 。我们建议增加一组 rMC，表达Fgf10（称为 rMC-Sca1 ^Pos Fgf10 ^Pos) 对维持 AT2 干细胞增殖同样重要。基于在生长因子减少的基质胶中的 AT2-rMC 共培养的肺泡球模型用于测试通过 FACS 从成年鼠肺中分离的不同 rMC 亚群维持 AT2 干细胞增殖和分化的效率。我们证明 rMC-Sca1 ^Pos Fgf10 ^Pos细胞可有效促进 AT2 干细胞的增殖和分化。成人肺分别对Fgf10 mRNA 和 Sftpc 蛋白进行共染色，表明 28% 的 Fgf10 ^Pos细胞位于 AT2 细胞附近。Fgf7和Fgf10的 Co-ISH表明这两个群体没有显着重叠。^{比较 rMC-Sca1 Pos} Axin2 ^Pos和 rMC-Sca1 ^Pos Fgf10 ^Pos的基因阵列支持这两个细胞亚群表达差异标记。此外，与 WT 小鼠相比，肥胖ob/ob突变体的 rMC 功能降低，雄性小鼠的功能丧失比雌性小鼠强得多。总之，rMC-Sca1 ^Pos Fgf10 ^Pos细胞在支持 AT2 干细胞增殖和分化中起重要作用。这一结果为 rMC 亚群在稳态和先前存在的代谢疾病的背景下有助于 AT2 干细胞生态位提供了新的线索。

更新日期：2021-05-28

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