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.
Highlights
Hematopoietic stem cells (HSCs) are rare subsets of hematopoietic cells that are responsible for life-long production of all blood cells lineages, and for the reconstitution of bone marrow (BM) after transplantation into myeloablated recipients[1,2]
The stem cell niche serves as a primary engraftment site for leukemic stem cells (LSCs) to initiate leukemogenesis, i.e., LSCs compete with normal HSCs during their engraftment into the BM niche[17,18]
We found that the proportions of mesenchymal stromal cells (CD45-Ter119-CD31−) in the BM was highest in the neonate, and decreased thereafter to adult levels by 2 weeks after birth (Fig. 1A)
Summary
Hematopoietic stem cells (HSCs) are rare subsets of hematopoietic cells that are responsible for life-long production of all blood cells lineages, and for the reconstitution of bone marrow (BM) after transplantation into myeloablated recipients[1,2]. Human leukemic diseases exhibit distinct clinical spectrums and incidence, and differences in their response to treatment between children and other age groups[33,34,35] It is unclear whether differences in the niche influence these age-related differences in the regenerative and leukemogenic activities of normal HSC and LSCs. The ontological changes in the microenvironment are important for many in vivo studies, since transplantation into the neonate BM niche is frequently employed as a model to explore the engraftment kinetics of HSCs and subsequent reconstitution of the immune system[36,37], because they achieve a higher level of engraftment than in adult models[38]. Despite this wide-spread use of the neonatal mice transplantation model, the specific influence of the neonatal BM microenvironment on HSCs or LSCs, compared to those of adult BM, has not been well established
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