Stem cell decoupling underlies impaired lymphoid development during aging

Mammalian aging is associated with multiple defects of hematopoiesis, most prominently with the impaired development of T and B lymphocytes. This defect is thought to originate in hematopoietic stem cells (HSCs) of the bone marrow, specifically due to the age-dependent accumulation of HSCs with pref...

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Published in:Proceedings of the National Academy of Sciences - PNAS 2023-05, Vol.120 (22), p.e2302019120-e2302019120
Main Authors: Jang, Geunhyo, Contreras Castillo, Stephania, Esteva, Eduardo, Upadhaya, Samik, Feng, Jue, Adams, Nicholas M, Richard, Elodie, Awatramani, Rajeshwar, Sawai, Catherine M, Reizis, Boris
Format: Article
Language:English
Subjects:
Aging
Aging (artificial)
Animals
Bias
Bone Marrow
Cell Differentiation
Cell Lineage
Decoupling
Defects
Gene sequencing
Hematopoiesis
Hematopoietic Stem Cells
Hemopoiesis
Lymphocytes
Lymphocytes B
Lymphopoiesis
Mammals
Mice
Myeloid cells
Progenitor cells
Progeny
Stem cells
Tracing
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Summary:Mammalian aging is associated with multiple defects of hematopoiesis, most prominently with the impaired development of T and B lymphocytes. This defect is thought to originate in hematopoietic stem cells (HSCs) of the bone marrow, specifically due to the age-dependent accumulation of HSCs with preferential megakaryocytic and/or myeloid potential ("myeloid bias"). Here, we tested this notion using inducible genetic labeling and tracing of HSCs in unmanipulated animals. We found that the endogenous HSC population in old mice shows reduced differentiation into all lineages including lymphoid, myeloid, and megakaryocytic. Single-cell RNA sequencing and immunophenotyping (CITE-Seq) showed that HSC progeny in old animals comprised balanced lineage spectrum including lymphoid progenitors. Lineage tracing using the aging-induced HSC marker confirmed the low contribution of old HSCs across all lineages. Competitive transplantations of total bone marrow cells with genetically marked HSCs revealed that the contribution of old HSCs was reduced, but compensated by other donor cells in myeloid cells but not in lymphocytes. Thus, the HSC population in old animals becomes globally decoupled from hematopoiesis, which cannot be compensated in lymphoid lineages. We propose that this partially compensated decoupling, rather than myeloid bias, is the primary cause of the selective impairment of lymphopoiesis in older mice.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.2302019120