Quantification of intrinsic regulatory factors refines human hematopoietic progenitor definitions and reveals early erythroid lineage priming. Quantification of intrinsic regulatory factors refines human hematopoietic progenitor definitions and reveals early erythroid lineage priming

Hematopoietic stem and progenitor cell (HSPC) transplantation is an essential therapy for the treatment of hematological conditions, but finer definitions of human HSPC subsets with associated function could enable better tuning of grafts and more routine application in patients with lower risks. To deeply characterize human HSPCs, we quantified 41 surface proteins and functional regulators on millions of CD34+ and CD34- cells, spanning four primary human hematopoietic tissues: bone marrow, mobilized peripheral blood, cord blood, and fetal liver. We propose more granular definitions of HSPC subsets and provide new, detailed differentiation trajectories of erythroid and myeloid lineages. These aspects of our revised human hematopoietic model were validated with corresponding epigenetic analysis and in vitro clonal differentiation assays. Overall, we demonstrate the utility of using molecular regulators as surrogates for cellular identity and functional potential, providing a framework for description, prospective isolation, and cross-tissue comparison of HSPCs in humans. Overall design: Chromatin accessibility profiling through ATAC sequencing of human bone marrow progenitors after sorting for specific populations in the erythrocyte and myeloid development stages

造血干祖细胞（hematopoietic stem and progenitor cell, HSPC）移植是治疗血液系统疾病的核心疗法，但对人类HSPC亚群及其关联功能进行更精准的定义，可实现移植物的优化调控，并推动其在低风险患者中的更常规临床应用。
为深入解析人类HSPC，我们对数百万个CD34+与CD34-细胞表面的41种表面蛋白及功能调控因子开展了定量表征，样本覆盖四种主要人类造血组织：骨髓、动员外周血、脐带血及胎肝。
本研究提出了更为细致的HSPC亚群划分标准，并构建了红系与髓系谱系全新的详细分化轨迹。
我们通过配套的表观遗传分析与体外克隆分化实验，对这一修正后的人类造血模型进行了验证。
总体而言，本研究证实了以分子调控因子作为细胞身份与功能潜能替代标志物的应用价值，为人类HSPC的描述、前瞻性分离以及跨组织比较提供了研究框架。
实验整体设计：针对红细胞与髓系发育阶段的特定细胞群体进行分选后，对人类骨髓祖细胞开展ATAC测序以进行染色质可及性分析。