Classically, hematopoietic stem cells (HSCs) were considered the sole source of fetal hematopoietic stem and progenitor cells in the fetal liver, forming the foundation of both fetal and adult hematopoiesis. However, recent fate-mapping studies challenge this dogma by identifying embryonic multipotent progenitors (eMPPs) as an independent population with a distinct origin from HSCs. Although both populations coexist in the fetal liver, their distinct functions, interrelationship, and contributions to postnatal immunity remain unclear.

Using complementary lineage-tracing models, we demonstrate a striking temporal and functional division of labor in which eMPPs are the primary drivers of hematopoiesis during late gestation, while HSCs, despite a dramatic ~20-fold expansion, contribute minimally to mature blood cells before birth. Between E12.5 and E16.5, fast-cycling eMPPs rapidly differentiate to sustain embryonic hematopoietic needs, generating specialized embryonic lymphocytes and lymphoid tissue inducer (LTi) cells that are indispensable for lymphoid organ development.

These findings support a refined model of fetal hematopoiesis in which eMPPs, rather than HSCs, are the principal source of immune effector cells during fetal life. This division of labor and stage-specific allocation of roles ensures timely establishment of the fetal immune system and proper lymphoid organ architecture, while safeguarding the long-term self-renewal and functional potential of the HSC pool for postnatal hematopoiesis.

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2025
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