ABSTRACT
Although bone marrow-derived mesenchymal stem cells (BM-MSCs) are widely recognized as promising therapeutic agents, the age-related impacts on cellular function remain largely uncharacterized. In this study, we found that BM-MSCs from young donors healed wounds in a xenograft model faster compared with their aged counterparts (p < .001). Given this significant healing advantage, we then used single-cell transcriptomic analysis to provide potential molecular insights into these observations. We found that the young cells contained a higher proportion of cells characterized by a higher expression of genes involved in tissue regeneration. In addition, we identified a unique, quiescent subpopulation that was exclusively present in young donor cells. Together, these findings may explain a novel mechanism for the enhanced healing capacity of young stem cells and may have implications for autologous cell therapy in the extremes of age. Stem Cells 2019;37:240-246.
Subject(s)
Mesenchymal Stem Cells/metabolism , Transcriptome/genetics , Adult , Aged , Aging , Animals , Cell Differentiation , Cell Proliferation , Cellular Senescence , Humans , Mice , Young AdultABSTRACT
Mechanisms underlying age-related defects within lymphoid-lineages remain poorly understood. We previously reported that sex steroid ablation (SSA) induced lymphoid rejuvenation and enhanced recovery from hematopoietic stem cell (HSC) transplantation (HSCT). We herein show that, mechanistically, SSA induces hematopoietic and lymphoid recovery by functionally enhancing both HSC self-renewal and propensity for lymphoid differentiation through intrinsic molecular changes. Our transcriptome analysis revealed further hematopoietic support through rejuvenation of the bone marrow (BM) microenvironment, with upregulation of key hematopoietic factors and master regulatory factors associated with aging such as Foxo1. These studies provide important cellular and molecular insights into understanding how SSA-induced regeneration of the hematopoietic compartment can underpin recovery of the immune system following damaging cytoablative treatments. These findings support a short-term strategy for clinical use of SSA to enhance the production of lymphoid cells and HSC engraftment, leading to improved outcomes in adult patients undergoing HSCT and immune depletion in general.
Subject(s)
Cell Differentiation , Gonadal Steroid Hormones/antagonists & inhibitors , Hematopoietic Stem Cells/cytology , Hematopoietic Stem Cells/metabolism , Lymphopoiesis/physiology , Regeneration , Animals , Cell Count , Cell Differentiation/genetics , Cell Movement , Cell Self Renewal , Gene Expression Profiling , Gene Expression Regulation, Developmental , Lymphoid Progenitor Cells/cytology , Lymphoid Progenitor Cells/metabolism , Male , Mice , Mice, Knockout , Models, Animal , Regeneration/genetics , Stem Cell NicheABSTRACT
Thymic epithelial cells (TECs) are critical for T cell development and self-tolerance but are gradually lost with age. The existence of thymic epithelial progenitors (TEPCs) in the postnatal thymus has been inferred, but their identity has remained enigmatic. Here, we assessed the entire adult TEC compartment in order to reveal progenitor capacity is retained exclusively within a subset of immature thymic epithelium displaying several hallmark features of stem/progenitor function. These adult TEPCs generate mature cortical and medullary lineages in a stepwise fashion, including Aire+ TEC, within fetal thymus reaggregate grafts. Although relatively quiescent in vivo, adult TEPCs demonstrate significant in vitro colony formation and self-renewal. Importantly, 3D-cultured TEPCs retain their capacity to differentiate into cortical and medullary TEC lineages when returned to an in vivo thymic microenvironment. No other postnatal TEC subset exhibits this combination of properties. The characterization of adult TEPC will enable progress in understanding TEC biology in aging and regeneration.
Subject(s)
Adult Stem Cells/physiology , Thymus Gland/cytology , Animals , Cell Lineage , Cell Proliferation , Cells, Cultured , Epithelial Cells/physiology , Male , Mice, Inbred C57BL , Mice, TransgenicABSTRACT
Most of the steps of lymphopoiesis have been elucidated but contentious issues remain, particularly regarding the identity and function of the earliest lymphoid progenitors that leave the bone marrow and seed the thymus. Hematopoiesis is effectively continuous throughout life, but there is a profound decline in immune function with increasing age, driven by thymus involution and severely curtailed B cell development. A key question is whether defects in bone marrow progenitors, such as reduced differentiation and repopulation potential, are the common denominator. While thymic involution temporally precedes overt HSC functional decline, a logical supposition is that the latter exacerbates the former. This review explores this possible link, and concludes that improving bone marrow function is fundamental to sustained thymic regeneration.
Subject(s)
Bone Marrow/immunology , Thymus Gland/immunology , Animals , Cell Differentiation , Cell Lineage , Hematopoietic Stem Cells/immunology , Humans , Thymus Gland/cytologyABSTRACT
The ability of stem cells to differentiate into various different cell types holds great promise for the treatment of irreversible tissue damage that occurs in many debilitating conditions. With stem cell research advancing at a tremendous pace, it is becoming clear that one of the greatest hurdles to successful stem cell-derived therapies is overcoming immune rejection of the transplant. Although the use of immunosuppressive drugs can decrease the incidence of acute graft rejection, the burden of problems associated with prolonged immunosuppression must be reduced. Strategies inducing specific immunological tolerance complemented by enhanced immune function will bring stem cell therapies closer to reality.