Key Points

  • CD34- MPP6 and CD34+ MPP5 (both LSK CD135- CD48- CD150-) are functionally located between HSCs and MPP2-4

  • Transplanted MPP5 are important for emergency myelopoiesis and long-term lymphoid reconstitution

Hematopoietic stem cells (HSCs) and distinct multipotent progenitor populations (MPP1-4) contained within the Lin- Sca-1+ c-Kit+ (LSK) compartment have previously been identified using diverse surface marker panels. Here, we phenotypically define and functionally characterize MPP5 (LSK CD34+ CD135- CD48- CD150-). Upon transplantation, MPP5 support initial emergency myelopoiesis followed by stable contribution to the lymphoid lineage. Since MPP5 are capable of generating MPP1-4, but not HSCs, they represent a dynamic and versatile component of the MPP network. To characterize all hematopoietic stem and progenitor cells (HSPCs), we performed RNA-seq analysis to identify specific transcriptomic landscapes of HSCs and MPP1-5. This was complemented by single-cell (sc) RNA-seq analysis of LSK cells to establish the differentiation trajectories from HSCs to MPP1-5. In agreement with the functional reconstitution activity, MPP5 are located immediately downstream of HSCs but upstream of the more committed MPP2-4. This study provides a comprehensive analysis of the LSK compartment, focusing on the functional and molecular characteristics of the newly defined MPP5 subset.

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