Department of Medical Oncology and Hematology, University Hospital and University of Zurich, 8091 Zurich, Switzerland.
Bioinformatics Unit, Spanish National Cancer Research Center (CNIO), 28029 Madrid, Spain.
Cell Rep. 2019 Dec 3;29(10):3313-3330.e4. doi: 10.1016/j.celrep.2019.11.004.
Bone marrow (BM) stromal cells provide the regulatory framework for hematopoiesis and contribute to developmental stage-specific niches, such as those preserving hematopoietic stem cells. Despite advances in our understanding of stromal function, little is known about the transcriptional changes that this compartment undergoes throughout lifespan and during adaptation to stress. Using RNA sequencing, we perform transcriptional analyses of four principal stromal subsets, namely CXCL12-abundant reticular, platelet-derived growth factor receptor (PDGFR)-αSca1, sinusoidal, and arterial endothelial cells, from early postnatal, adult, and aged mice. Our data reveal (1) molecular fingerprints defining cell-specific anatomical and functional features, (2) a radical reprogramming of pro-hematopoietic, immune, and matrisomic transcriptional programs during the transition from juvenile stages to adulthood, and (3) the aging-driven progressive upregulation of pro-inflammatory gene expression in stroma. We further demonstrate that transcriptomic pathways elicited in vivo by prototypic microbial molecules are largely recapitulated during aging, thereby supporting the inflammatory basis of age-related adaptations of BM hematopoietic function.
骨髓（BM）基质细胞为造血提供了调节框架，并有助于发育阶段特异性龛位，例如维持造血干细胞的龛位。尽管我们对基质功能的理解有所进展，但对于这个细胞群在整个生命周期中以及在适应压力时经历的转录变化知之甚少。我们使用 RNA 测序，对来自新生后、成年和老年小鼠的四个主要基质细胞亚群，即 CXCL12 丰富的网状细胞、血小板衍生生长因子受体（PDGFR）-αSca1、窦状内皮细胞和动脉内皮细胞，进行转录分析。我们的数据揭示了：（1）定义细胞特异性解剖和功能特征的分子特征；（2）从幼年到成年过渡过程中，造血、免疫和基质转录程序的彻底重编程；（3）衰老驱动的基质中促炎基因表达的渐进上调。我们进一步证明，在体内引发的典型微生物分子的转录途径在衰老过程中得到了很大程度的再现，从而支持了骨髓造血功能与年龄相关的适应性的炎症基础。
