Age-related differences in the bone marrow stem cell niche generate specialized microenvironments for the distinct regulation of normal hematopoietic and leukemia stem cells

Abstract

The bone marrow (BM) microenvironment serves as a stem cell niche regulating the in vivo cell fate of normal hematopoietic stem cells (HSC) as well as leukemia stem cells (LSCs). Accumulating studies have indicated that the regeneration of normal HSCs and the process of leukemogenesis change with advancing age. However, the role of microenvironmental factors in these age-related effects are unclear. Here, we compared the stem cell niche in neonatal and adult BM to investigate potential differences in their microenvironmental regulation of both normal and leukemic stem cells. We found that the mesenchymal niche in neonatal BM, compared to adult BM, was characterized by a higher frequency of primitive subsets of mesenchymal stroma expressing both platelet-derived growth factor receptor and Sca-1, and higher expression levels of the niche cross-talk molecules, Jagged-1 and CXCL-12. Accordingly, normal HSCs transplanted into neonatal mice exhibited higher levels of regeneration in BM, with no difference in homing efficiency or splenic engraftment compared to adult BM. In contrast, in vivo self-renewal of LSCs was higher in adult BM than in neonatal BM, with increased frequencies of leukemia-initiating cells as well as higher lympho-myeloid differentiation potential towards biphenotypic leukemic cells. These differences in LSC self-renewal capacity between neonates and adults was abrogated by switching of recipients, confirming their microenvironmental origin. Our study provides insight into the differences in leukemic diseases observed in childhood and adults, and is important for interpretation of many transplantation studies involving neonatal animal models.

Efficacy and safety of stem cell therapy for the early-stage osteonecrosis of femoral head: a systematic review and meta-analysis of randomized controlled trials

“…Besides, the microenvironment of bone marrow could be quite different among different ages which also affect the potential and biodistribution of stem cells. Several researchers investigated that older patients usually have complicated microenvironment changes characterized with dysregulation of metabolism and immune system influenced by various epigenetic factors and signaling networks [45][46][47][48]. In addition, different from our results, a previously [6] published guideline on ONFH suggested that effectiveness of stem cells are limited on preserving joint and the revision was relative high due to young patients.…”

Common and different alterations of bone marrow mesenchymal stromal cells in myelodysplastic syndrome and multiple myeloma

“…When analyses were limited in patients, age and telomere length were not different according to degree of proliferation nor between disease category. We postulated that age was associated with physiological senescence of BM‐MSCs including telomere shortening, decreased proliferation activity and haematopoiesis support function rather than premature impairment of proliferation which was seen in patients 19‐22 . Interestingly, CXCL12 expression was low in poor proliferating MSCs, which functions HSC maintenance and regulation including quiescence and the ability to induce multilineage reconstitution 23 .…”

Human Aging Alters the Spatial Organization between CD34+ Hematopoietic Cells and Adipocytes in Bone Marrow

“…Numerous mouse studies have shown that hematopoietic stem cells (HSCs) lose their repopulation capacity while increasing their quiescence and frequency with aging ( de Haan et al., 1997 ; Rossi et al., 2005 ). Aging also favors myeloid, megakaryocytic, and erythroid over lymphoid lineages ( Cho et al., 2008 ; Rundberg Nilsson et al., 2016 ), which has been linked to the influence of intrinsic ( Beerman et al., 2010 ; Chambers et al., 2007 ; Rossi et al., 2005 ) and microenvironmental factors ( Ergen et al., 2012 ; Lee et al., 2019 ; Vas et al., 2012 ). In mouse models, bone marrow (BM) microenvironmental populations that have been reported to be essential for hematopoietic regulation include osteoblasts, endothelial cells, bone marrow stromal cells (BMSCs), and adipocytes ( Acar et al., 2015 ; Ding et al., 2012 ; Ding and Morrison, 2013 ; Zhou et al., 2017 ).…”