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Niche alterations promoting hematopoietic aging
HSC aging, provide hypotheses for BM niche remodeling based on current knowledge, and discuss the potential implications for age-related myeloid malignancies. HSC- intrinsic aging mechanisms are the focus of a separate complementary review in this issue of Haematologica and will not be discussed here.
Evolving views on hematopoietic stem cell niches
HSC are surrounded by numerous cell types and the associated extracellular matrix in the BM, which form a unique microenvironment known as the “HSC niche’’. Osteoblasts were the first niche cells found to be involved in hematopoiesis. Early studies indicated that osteoblasts differentiate from BM osteoprogenitor cells, secrete hematopoietic cytokines and can maintain HSC in culture.20 In 2003, two studies described for the first time that transplanted HSC localize to the bone surface of BM and their numbers are regulated by osteoblastic cells. Long-term HSC were found to adhere to spindle-shaped N-cadherin+CD45- osteoblastic (SNO) cells, which control HSC size by BMP signaling.21 A recent study has shown that N-cadherin+ cells maintain a population of highly qui- escent reserve HSC,22 suggesting the possibility that differ- ent BM niches might regulate steady-state vs. stress hematopoiesis. Another study showed that osteoblasts activated with parathyroid hormone/parathyroid hor- mone-related protein receptor produce high levels of Notch ligand Jagged 1 and increase HSC numbers.23 Later studies further identified Tie2/angiopoietin-1 signaling and thrombopoietin/MPL signaling as important regula-
tors of HSC quiescence through interactions with osteoblasts.24,25 A high calcium concentration in the endos- teum also plays an indispensable role, maintaining HSC in the endosteal niche, since calcium-sensing receptor knock- out HSC fail to migrate to the endosteal BM surface after transplantation.26 In addition, the endosteal BM area is enriched in CXCL1227 and stem cell factor,28 two of the most important molecules supporting hematopoiesis, strengthening the hypothesis that the endosteum is a major reservoir for HSC. However, the osteoblastic niche was thereafter challenged in studies in which osteoblastic- specific deletion of Cxcl12 or Scf only affected the main- tenance of early lymphoid progenitors but had little impact on HSC.29 Furthermore, N-cadherin expression in osteolineage cells seems to be dispensable for HSC main- tenance under homeostasis.30 Whereas N-cadherin might not be essential for HSC, N-cadherin+ cells appear neces- sary to maintain a reservoir population of quiescent HSC.22 Studies on these aspects raise the possibility that different niches might exist for activated/quiescent HSC, and/or for HSC contributing to steady-state/emergency hematopoiesis. The BM is highly vascularized, and the close developmental relationship between hematopoietic and endothelial lineages together suggest that HSC are housed and regulated in perivascular regions. To date, at least two functionally distinct perivascular niches that highly express Cxcl12 and Scf to dictate HSC cell fate have been identified in mice: (i) the arteriolar niches, composed mainly of arterioles (found throughout the BM) or endosteal transition-zone vessels, both of which are asso- ciated with sympathetic nerve fibers, Nestin-GFPbright and/or NG2+ cells; and (ii) the sinusoidal niches, where sinusoid-associated Cxcl12-abundant reticular cells,
Figure 1. Schematic model of the interplay between hematopoietic stem cells and the microenvironment during aging. Loss of β3-adrenergic receptor ( β3-AR) activ- ity reduces endosteal niches, pushes hematopoietic stem cells (HSC) away from the endosteum and favors myeloid bias at the expense of lymphopoiesis. Accumulation of aged HSC in the central bone marrow and increased β2-AR activity causes expansion of central capillaries, myeloid cells and megakaryocytes, which locate farther from HSC.
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