Clonal Analyses Reveal the Impact of Hematopoietic Stem and Progenitor Cell Aging on T Cell Development.

Julia Gensheimer, Jessica LaGosh, Emma R Moulton, Victoria Sun, Stephanie C de Barros, Encarnacion Montecino-Rodriguez, Gloria Yiu, Xuegang Yuan, Kenneth Dorshkind, Gay M Crooks

Molecular Biology Interdepartmental Program, University of California, Los Angeles, Los Angeles, California, USA.Molecular Biology Interdepartmental Program, University of California, Los Angeles, Los Angeles, California, USA. · pubmed

Paper

Abstract

T cell output from the thymus falls throughout life and is associated with profound remodeling of the thymic stroma. To what extent the decline in T cell output is caused by aging of the hematopoietic stem and progenitor cells (HSPCs) has been difficult to define because of HSPC heterogeneity, the multi-stage process of HSPC migration, and the cross-talk between hematopoietic and stromal elements of the thymus. To address the contribution of HSPC aging on T cell development, we interrogated T cell differentiation of phenotypically defined HSPCs from young and aged bone marrow using the Artificial Thymic Organoid (ATO) system, an in vitro model which allows quantification of T cell differentiation from single HSPCs within a controlled microenvironment. Phenotypically, most HSCs from young bone marrow were CD150

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Research summary

The study utilizes an in vitro organoid system to demonstrate that intrinsic aging of hematopoietic stem and progenitor cells contributes to the decline in thymic T cell output, providing mechanistic insight into immunosenescence. This work is relevant as it addresses a fundamental root cause of aging—the functional decline of stem cells—rather than merely treating symptoms, although its impact is limited by its focus on a specific lineage and the use of an artificial model that may not fully capture in vivo complexity.

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