Bcl11a orchestrates multilineage integrity in aging hematopoiesis by regulating multipotent progenitor fate decisions.
Abstract
Aging hematopoiesis exhibits progressive myeloid skewing and impaired lymphopoiesis, driving age-related blood disorders. We show that multipotent progenitors (MPPs) mediate this lineage imbalance. Aging expands myeloid-biased MPP3 cells while functionally compromising MPP4 lymphoid potential, collectively skewing hematopoietic output toward the myeloid lineage. We identify Bcl11a as a dosage-sensitive regulator of MPP fate: Bcl11a suppresses Fer to restrain premature myeloid differentiation in MPP3, while activating the Irf8-Ebf1 axis to license lymphoid specification. Strikingly, sustained Bcl11a elevation from development preserves balanced lineage output into old age, reverses age-associated transcriptional alterations, and restores multilineage reconstitution capacity. These findings establish Bcl11a as a key molecular guardian of progenitor integrity during aging and underscore MPPs as a critical cellular nexus where transcriptional control translates into lineage fate decisions.
The following analysis is generated by AI and may contain errors. It is separate from the authors’ abstract and is not peer review.
Research summary
Sustained elevation of Bcl11a in multipotent progenitors preserves balanced hematopoietic lineage output and reverses age-associated transcriptional alterations, thereby maintaining multilineage reconstitution capacity in aging. This paper is relevant because it identifies a specific molecular mechanism (Bcl11a dosage) that directly counteracts a fundamental hallmark of aging (hematopoietic stem cell skewing and functional decline), offering a potential strategy to restore tissue homeostasis rather than merely treating symptoms.
Author of this paper? Send a correction.