SUMMARY Multipotent stromal cells (MSC) and their osteoblastic lineage cell (OBC) derivatives are part of the BM niche and contribute to hematopoietic stem cells (HSC) maintenance. Here, we show that myeloproliferative neoplasia (MPN) progressively remodels the endosteal BM niche into a self-reinforcing leukemic niche that impairs normal hematopoiesis, favors leukemic stem cell (LSC) function and contributes to BM fibrosis. We show that leukemic myeloid cells stimulate MSCs to overproduce functionally altered OBCs, which accumulate in the BM cavity as inflammatory myelofibrotic cells. We identify roles for TPO, CCL3 and direct cell-cell interactions in driving OBC expansion, and for changes in TGFβ, Notch and inflammatory signaling in OBC remodeling. MPN-expanded OBCs, in turn, exhibit decreased expression of many HSC retention factors and severely compromised ability to maintain normal HSCs, but effectively support LSCs. Targeting this pathological interplay could represent a novel avenue to treat MPN patients and prevent myelofibrosis.
Blood production is ensured by rare self-renewing hematopoietic stem cells (HSCs). How HSCs accommodate the diverse cellular stresses associated with their life-long activity remains elusive. Here, we identify autophagy as an essential mechanism protecting HSCs from metabolic stress. We show that HSCs, in contrast to their short-lived myeloid progeny, robustly induce autophagy following ex vivo cytokine withdrawal and in vivo caloric restriction. We demonstrate that FoxO3a is critical to maintain a gene expression program that poise HSCs for rapid induction of autophagy upon starvation. Notably, we find that old HSCs retain an intact FoxO3a-driven pro-autophagy gene program, and that ongoing autophagy is needed to mitigate an energy crisis and allow their survival. Our results demonstrate that autophagy is essential for the life-long maintenance of the HSC compartment and for supporting an old, failing blood system.
IntroductionHematologic malignancies account for ϳ 9% of all newly diagnosed cancers in the United States. 1 Changes in hematopoiesis also occur in many medical conditions and significantly contribute to morbidity and mortality. Although blood disorders arise primarily from defects in hematopoietic cells, contextual signals from stromal cells in the BM microenvironment or "niche" may also influence disease development.Adult hematopoiesis occurs in the BM where multipotent hematopoietic stem cells (HSCs) generate all lineages of mature blood cells through a hierarchy of developmentally restricted progenitor populations. 2 HSCs reside in specialized niches formed by different stromal populations, including endothelial cells (ECs), mesenchymal stem cells (MSCs), and osteoblastic-lineage cells (OBCs), which express key HSC-supportive factors, including Notch ligands, Cxcl12, and angiopoietin-1 (Angpt1). 3,4 Although early mouse studies have implicated mature osteoblasts as important regulators of HSC numbers, 5-7 more recent work has shown that immature OBCs and perivascular MSCs are in fact the major BM niche constituents ensuring HSC maintenance. [8][9][10] Coculture experiments have also demonstrated the functional importance of interactions with ECs and OBCs in regulating blood production by HSCs. 11,12 These findings indicate that ECs, OBCs, and MSCs are 3 essential BM stromal cell populations that regulate HSC activity and blood homeostasis.Recent work has also illustrated how changes in BM stromal cells contribute to the development of hematologic diseases. Genetic ablation of the retinoblastoma, 13 retinoic acid receptor gamma, 14 or miRNA processing enzyme Dicer 15 genes in BM stromal cells or osteoprogenitor cells all resulted in dysfunctional BM niches promoting myeloproliferative neoplasms or myelodysplastic syndromes. Furthermore, the loss of G s G-protein-coupled receptor (GPCR) signaling in osteoprogenitor cells was found to impair B-cell development. 16 These examples stress the role of BM stromal niche cells in regulating hematopoiesis and indicate that appropriate GPCR signals are crucial for normal blood development.Surprisingly little is known about how abnormal G s -GPCR signaling in osteoblastic cells affects hematopoiesis. Activation of the key osteoblast G s GPCR parathyroid hormone receptor 1 (PTHR1) by parathyroid hormone (PTH) causes changes in osteoblast proliferation, differentiation, and function. 17 Clinically, daily injection of recombinant PTH is used to increase bone formation for osteoporosis treatment. 18 Recently, PTH injections were also shown to increase both HSC mobilization and engraftment in mouse models of BM transplantation. 5,19,20 These studies have led to clinical trials using PTH to enhance HSC-based therapies 21 and raised the exciting possibility of improving HSC function by modulating osteoblast factors, particularly via GPCR signals.The complexity of the G s ␣ gene locus, embryonic lethality of G s ␣ overactivity, and genetic imprinting of this locus pose significa...
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