From:  Hematopoietic and leukemic stem cells homeostasis: the role of bone marrow niche

Summary of different cell types and their role in the normal and leukemic HSC niches

Cell typeSecreted or expressed factors (molecular pathways)Healthy nicheAML nicheAltered molecular pathways
Non-hematopoietic cells
Osteoblasts

  • CSF3

  • BMPRIA

  • Osteopontin/CD44

  • Control HSC expansion and self-renewal

  • Regulation of HSC homing, quiescence, and mobilization

  • Control the generation of adaptive immune cells

  • AML decreases osteoblast production

  • AML decrease OSP

  • AML increases CD44 expression

Unchecked activation of the RANK/RANKL pathway
OsteocytesCSF3 (indirect way)Regulation of osteoblast--
Nestin+ mesenchymal cells

  • CXCL12

  • SCF

  • Differentiation to osteoblast, chondrocytes and adipocytes

  • Enhance HSC differentiation and maintenance of HSC

  • Mediate sympathetic circadian signaling to HSC

  • MSCs increase CD271+ MSCs JAG1

  • MSCs decrease SCF

  • Enhancement of BM homing of AML LSCs

  • Supporting low proliferative but highly resistant LSCs

CXCL12/CXCR4
CAR cellsCXCL12

  • Maintaining HSC

  • Maintaining lymphoid progenitors

  • CXCR4 expression is increased by AML blast

  • CXCL12 secretion is increased by CAR cells

  • CXCL12/CXCR4

  • Activation of JAK/STAT, PI3K/AKT, and MEK/ERK pathways through CXCL12/CXCR4

Non-myelinating Schwann cellsTGFB (SMAD) signalsHSC quiescenceDisruption of nestin GFP+ cell quiescence-
SNSCatecholaminesControlling the cyclical circadian release of HSCsSNS denervation enhances leukemic cell proliferationAltered B2-adrenergic pathway
AdipocytesAdiponectinNegative regulators of homeostatic

  • AML cells increase lipolysis

  • AML cells increase FAO

  • GDF15 is highly expressed by LSCs

  • Upregulation of PPARG, FABP4, and BCL2 genes by LSCs

Endothelial cells

  • Selectin E

  • Selectin P

  • VCAM1

  • Express Notch ligands

  • Doorkeeper

  • Maintaining HSCs

  • Increase HSC quiescence and self-renewal

  • Promote adhesion of LSCs

  • Stimulates AML cells and proliferation

  • Angiogenesis

  • Notch pathway

  • CD44/Selectin E

  • VLA4/VCAM1

  • DLL4 pathway

Hematopoietic cells
Osteoclast

  • RANKL pathway

  • Proteolytic enzymes

  • Maintenance of the endosteal niche cavities

  • HSC mobilization

  • Osteoclast depletion is associated with an increase in EH

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Macrophages

  • Oncostatin M

  • Prostaglandin E2

  • HSCs mobilization

  • HSCs retention in the endosteal niche

  • Macrophages increase CXCL12/CXCR4 by nestin+ MSCs

  • Promote Erythropoiesis

LAM helps in chemotherapeutic resistance-
Lymphocytes-

  • Regulation of hematopoietic stem cell growth

  • T-regs play a crucial role in immune tolerance

  • T-regs create a protective zone from the immune attack

  • AML dysregulates T-cells

  • AML evades detection by NK cells

  • Exhaustion of CD8+ T-cells

  • Dysregulation in Th1/Th2 axis

  • Increase in dysregulation in Th1/Th2 axis and its cytokines

  • AML increase T-regs

  • AML stimulates T-regs

  • TIM3/LGALS9

  • ICOSLG

NeutrophilsIndirect role mediated by macrophagesClearance of aged neutrophils by macrophages regulates HSCs mobilization--
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HSC: hematopoietic stem cell; AML: acute myeloid leukemia; RANK: receptor activator of nuclear factor κB; RANKL: receptor activator of nuclear factor κB ligand; MSCs: mesenchymal stromal cells; BM: bone marrow; LSCs: leukemic stem cells; CAR: CXCL12-abundant reticular; TGFB: transforming growth factor-beta; GFP: green fluorescent protein; FAO: fatty acid β-oxidation; EH: extramedullary hematopoiesis; LAM: leukemia-associated macrophage; NK: natural killer; T-regs: regulatory T-cells; BMPRIA: bone morphogenetic protein receptor type IA; VCAM1: vascular adhesion molecule 1; SNS: sympathetic nervous system; VLA4: very late antigen 4; GDF15: growth differentiation factor 15; OSP: osteopontin. -: no data