Single-cell profiling of the human bone marrow stromal cells in clonal hematopoiesis and myelodysplasia

Somatic mutations in hematopoietic stem/progenitor cells (HSPCs) can lead to clonal hematopoiesis of indeterminate potential (CHIP) and progression to myelodysplastic syndromes (MDS). Using single-cell and anatomical profiling of a large cohort of human bone marrow (BM), we show that the HSPC BM niche in CHIP and MDS is undergoing inflammatory remodeling. This includes loss of CXCL12⁺ adipogenic stromal cells and the emergence of a distinct population of inflammatory mesenchymal stromal cells (iMSCs), which arise in CHIP and become more prevalent in MDS. Functional studies in primary BM HSPC-MSC co-cultures reveals that healthy aged and CHIP HSPCs activate stromal support, while MDS HSPCs fail to do so. In contrast, MDS blasts further suppress HSPC support and trigger inflammation, indicating disease-stage-specific stromal disruption. In parallel, we show that iMSCs retain partial support and angiogenic potential in MDS, coinciding with expanded BM vasculature. Additionally, we identify IFN-responsive T cells that preferentially interact with iMSCs, potentially reinforcing local inflammation. These findings position iMSCs as central mediators of early BM niche dysfunction and potential therapeutic targets for intercepting pre-malignant hematopoiesis. Stromal cells isolated using FACS were analysed with scRNA-seq.

造血干/祖细胞（hematopoietic stem/progenitor cells, HSPCs）的体细胞突变可导致意义未明的克隆性造血（clonal hematopoiesis of indeterminate potential, CHIP），并进展为骨髓增生异常综合征（myelodysplastic syndromes, MDS）。本研究针对大型人类骨髓（bone marrow, BM）队列开展单细胞与解剖特征谱分析，结果显示CHIP与MDS患者的HSPC骨髓龛正发生炎症性重塑，该重塑包括CXCL12阳性脂肪生成基质细胞的丢失以及一类独特的炎症性间充质基质细胞（inflammatory mesenchymal stromal cells, iMSCs）的出现；这类细胞在CHIP阶段即已产生，并在MDS阶段的占比进一步升高。对原代骨髓HSPC-MSC共培养体系的功能研究表明，健康老年个体与CHIP患者的HSPC可激活基质细胞的支持功能，而MDS患者的HSPC则无法实现这一过程。与之相反，MDS原始细胞会进一步抑制HSPC的基质支持功能并诱发炎症，提示基质细胞的紊乱具有疾病分期特异性。与此同时，我们发现MDS阶段的iMSCs仍保留部分支持功能与血管生成潜能，这与骨髓血管系统的扩张相契合。此外，本研究还鉴定出一类优先与iMSCs相互作用的干扰素应答性T细胞，该细胞群可能会加剧局部炎症反应。上述研究结果证实，iMSCs是早期骨髓龛功能异常的核心介导因子，同时也是干预癌前造血过程的潜在治疗靶点。研究人员通过荧光激活细胞分选术（fluorescence-activated cell sorting, FACS）分离得到基质细胞，并采用单细胞RNA测序（single-cell RNA sequencing, scRNA-seq）对其进行分析。