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Bcl11a orchestrates multilineage integrity in aging hematopoiesis by regulating multipotent progenitor fate decisions

Linlin Zhang1, Xiang Xu1, Jing Wang1

  • 1Department of Hematology, Tongji Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.

Cell Reports
|July 20, 2026
PubMed

Insights

Aging impairs blood cell formation, favoring myeloid cells. Bcl11a protein maintains balanced blood cell production by regulating multipotent progenitors (MPPs), preventing age-related blood disorders.

Area of Science:

  • Hematology
  • Developmental Biology
  • Aging Research

Background:

  • Aging hematopoiesis shows a myeloid skew and reduced lymphopoiesis, leading to blood disorders.
  • Multipotent progenitors (MPPs) are central to this age-related lineage imbalance.
  • Aging expands myeloid-biased MPP3 cells and impairs MPP4 lymphoid potential.

Purpose of the Study:

  • To investigate the role of multipotent progenitors (MPPs) in age-related hematopoietic lineage skewing.
  • To identify molecular regulators governing MPP fate decisions during aging.
  • To explore therapeutic strategies for restoring hematopoietic function in aging.

Main Methods:

  • Analysis of hematopoietic stem and progenitor cell populations in young and aged mice.
  • Transcriptional profiling and functional assays of MPP subsets (MPP3 and MPP4).
  • Genetic manipulation of Bcl11a expression in hematopoietic stem cells.

Main Results:

  • Aging leads to an expansion of myeloid-biased MPP3 cells and a functional decline in MPP4 lymphoid potential.
  • Bcl11a acts as a dosage-sensitive regulator, suppressing Fer in MPP3 and activating the Irf8-Ebf1 axis in MPP4.
  • Sustained Bcl11a elevation prevents age-associated transcriptional changes and restores multilineage reconstitution capacity.

Conclusions:

  • Bcl11a is a critical regulator of progenitor integrity, maintaining balanced hematopoiesis during aging.
  • MPPs are a key cellular target for interventions aimed at mitigating age-related hematopoietic decline.
  • Targeting Bcl11a may offer a strategy to combat age-related blood disorders.
Keywords:
Bcl11aCP: stem cell researchaginghematopoiesisimmune reconstitutionlineage fatemultipotent progenitors

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