Aging alters bone-fat reciprocity by shifting in vivo mesenchymal precursor cell fate towards an adipogenic lineage

Abstract

Bone marrow derived mesenchymal progenitor cells (MPCs) play an important role in bone homeostasis. Age-related changes occur in bone resulting in a decrease in bone density and a relative increase in adipocity. Although in vitro studies suggest the existence of an age-related lineage switch between osteogenic and adipogenic fates, stem cell and microenvironmental contributions to this process have not been elucidated in vivo. In order to study the effects of MPC and microenvironmental aging on functional engraftment and lineage switching, transplantation studies were performed under non-myeloablative conditions in old recipients, with donor MPCs derived from young and old green fluorescent protein (GFP) transgenic mice. Robust engraftment by young MPCs or their progeny was observed in the marrow, bone-lining region and in the matrix of young recipients; however, significantly lower engraftment was seen at the same sites in old recipients transplanted with old MPCs. Differentiation of transplanted MPCs strongly favored adipogenesis over osteogenesis in old recipients irrespective of MPC donor age, suggesting that microenvironmental alterations that occur with in vivo aging are predominately responsible for MPC lineage switching. These data indicate that aging alters bone-fat reciprocity and differentiation of mesenchymal progenitors toward an adipogenic fate.

Inflamm-Aging of Hematopoiesis, Hematopoietic Stem Cells, and the Bone Marrow Microenvironment

“…MSCs are characterized by plastic adherence, high growth potential, and mesenchymal immunophenotypes, as well as differentiation into mesenchymal lineages, such as osteocytes, adipocytes, chondrocytes, fibroblasts, and epithelial cells (60, 61). Aged MSCs exhibit reduced clonogenic and proliferative capacity, and differentiation potentials are skewed toward adipogenesis at the expense of osteogenesis (62–64). These cells also show enlargement, telomere shortening, or p53/p21-mediated DNA damage accumulation, impaired DNA methylation or histone acetylation, and increased levels of ROS and nitric oxide (NO) (65–69).…”

Development, regulation, metabolism and function of bone marrow adipose tissues

“…Both of these studies suggest that irradiation-induced BMAs are generated from recipient precursors rather than from donor cells. Interestingly, without irradiation, transplanted mesenchymal progenitor cells homed to marrow and developed into many of the BMAs observed in older recipient mice 73 .…”

Microenvironmental Views on Mesenchymal Stem Cell Differentiation in Aging

“…A more critical functional compromise of BMMSCs in aging is impaired osteogenesis with misdirected differentiation toward adipocytes, a key process involved in the pathogenesis of osteoporosis . Notably, a recent study revealed that after transplantation into old recipient mice, the differentiation of BMMSCs shifted toward adipogenesis rather than osteogenesis irrespective of donor age, indicating that microenvironmental impacts are predominately responsible for MSC lineage switching in aging (Singh et al 2016). Further studies have shown that the age of donors also limits the regenerative capacity of MSCs in ectopic positions (Zhang et al 2012), inhibits their immunoregulatory potential in autoimmune diseases (Scruggs et al 2013), and abrogates their neurotrophic activity (Brohlin et al 2012), which might be due to an altered cytokine secretion of MSCs ( Fig.…”