Elucidating the mechanisms underlying hematopoietic stem cell (HSC) specification and expansion in the embryo has been hampered by the lack of analytical cell culture systems that recapitulate in vivo development. Here, we describe an ex vivo model that facilitates a rapid and robust emergence of multipotent long-term repopulating HSCs in the embryonic AGM region. Because this method includes a cell dissociation step prior to reconstruction of a three-dimensional functional tissue and preserves both stromal and hematopoietic elements, it allowed us to identify the direct ancestry of the rapidly expanding HSC pool. We demonstrate that extensive generation of definitive HSCs in the AGM occurs predominantly through the acquisition of stem characteristics by the VE-cadherin+CD45+ population.
T cell differentiation and repertoire selection depend critically on several distinct thymic epithelial cell types, whose lineage relationships are unclear. We have investigated these relationships via functional analysis of the epithelial populations within the thymic primordium. Here, we show that mAbs MTS20 and MTS24 identify a population of cells that, when purified and grafted ectopically, can differentiate into all known thymic epithelial cell types, attract lymphoid progenitors, and support CD4(+) and CD8(+) T cell development in nude mice. In contrast, other epithelial populations in the thymic primordium can fulfill none of these functions. These data establish that the MTS20(+)24(+) population is sufficient to generate a functional thymus in vivo and thus argue strongly that all thymic epithelial cell types derive from a common progenitor cell.
Aging is associated with decreased immune function that leads to increased morbidity and mortality in the elderly. Immune senescence is accompanied by age-related changes in two primary lymphoid organs, bone marrow and thymus, that result in decreased production and function of B and T lymphocytes. In bone marrow, hematopoietic stem cells exhibit reduced self-renewal potential, increased skewing toward myelopoiesis, and decreased production of lymphocytes with aging. These functional sequelae of aging are caused in part by increased oxidative stress, inflammation, adipocyte differentiation, and disruption of hypoxic osteoblastic niches. In thymus, aging is associated with tissue involution, exhibited by a disorganization of the thymic epithelial cell architecture and increased adiposity. This dysregulation correlates with a loss of stroma-thymocyte ‘cross-talk’, resulting in decreased export of naïve T cells. Mounting evidence argues that with aging, thymic inflammation, systemic stress, local Foxn1 and keratinocyte growth factor expression, and sex steroid levels play critical roles in actively driving thymic involution and overall adaptive immune senescence across the lifespan. With a better understanding of the complex mechanisms and pathways that mediate bone marrow and thymus involution with aging, potential increases for the development of safe and effective interventions to prevent or restore loss of immune function with aging.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.