A novel lymphoid-primed progenitor marked by Dach1 downregulation identified with single cell multi-omics

A classical view of blood cell development is that multipotent haematopoietic stem and progenitor cells (HSPCs) become lineage-restricted at defined stages. The Lin–c-kit+Sca1+Flt3+ stage, termed lymphoid-primed multipotent progenitors (LMPPs), have lost megakaryocyte and erythroid potential but are heterogeneous in their fate. Through single cell RNA-sequencing, we identify heterogeneous expression of Dach1 and associated genes in this fraction where it co-expressed with myeloid/stem genes but inversely correlated with lymphoid genes. Through generation of Dach1-GFP reporter mice, we identify a transcriptionally and functionally unique Dach1– subpopulation within LMPPs with lymphoid potential but devoid of myeloid potential. We term these ‘lymphoid-primed progenitors’, or LPPs. These findings define the earliest branch point of lymphoid development in haematopoiesis and a means for their prospective isolation.

经典的血细胞发育理论认为，多能造血干细胞和祖细胞（multipotent haematopoietic stem and progenitor cells, HSPCs）会在特定阶段获得谱系限制性。Lin⁻c-kit⁺Sca1⁺Flt3⁺ 表型细胞群被称为淋巴系定向多能祖细胞（lymphoid-primed multipotent progenitors, LMPPs），其已丧失巨核细胞与红细胞系分化潜能，但细胞命运决定仍具有异质性。通过单细胞RNA测序，我们在该细胞组分中鉴定出Dach1及相关基因的异质性表达模式：Dach1与髓系/干细胞基因共表达，却与淋巴系基因呈负相关。通过构建Dach1-GFP报告基因小鼠，我们在LMPPs群中鉴定出一个转录特征与功能均独特的Dach1⁻亚群，该亚群仅具备淋巴系分化潜能，而无髓系分化潜能。我们将其命名为‘淋巴系定向祖细胞（lymphoid-primed progenitors, LPPs）’。本研究明确了造血过程中淋巴系发育的最早分支点，并提供了其前瞻性分离的手段。