Ecological insights into hematopoiesis regulation: unraveling the influence of gut microbiota

Figures & data

Figure 1. Hematopoietic differentiation hierarchy.

HSCs are at the apex of a hierarchy of multiple progenitor cell stages giving rise to all blood cell lineages.

EB, embryo; HEC, hemogenic endothelial cells; EHT, endothelial-to-hematopoietic transition; HSC, hematopoietic stem cell; MPP, multipotent progenitor; LMPP, lymphoid-primed MPP; CLP, common lymphoid progenitor; CMP, common myeloid progenitor; MEP, megakaryocyte-erythroid progenitor; GMP, granulocyte-monocyte progenitor; CDP, common dendritic progenitor; MKP, megakaryocyte progenitor; NK, natural killer cell.

Table 1. Cellular and molecular constituents of the HSC niche.

Cell type	Soluble/membrane-bound niche factor	Cell phenotype	Effects on hematopoiesis
LepR^+ stromal cells	SCF PTN^Citation31 CXCL12	Perivascular cells that express high levels of CXCL12 and SCF	Maintain HSCs^Citation20 and c-kit restricted hematopoietic progenitors^Citation32
Nes-GFP^+ stromal cells	SCF CXCL12^Citation29	Nes-GFP^bright cells along with arterioles and Nes-GFP^dim cells associated with sinusoids	Maintain HSCs^Citation33,Citation34 Regulate erythropoiesis^Citation35 HSCs mobilization and homing^Citation36,Citation37 HSCs expansion^Citation38
NG2^+ stromal cells	CXCL12	Periarteriolar labeled by NG2 pericyte marker^Citation33	Promote HSCs quiescence^Citation39
CAR cells	IL-6 SCF CXCL12	Cells that express high levels of CXCL12 and SCF	Sensing and integrating signals produced by pathogens for hematopoiesis under chronic inflammation^Citation40 HSC maintenance^Citation41
N-Cadherin^+ stromal cells	SCF CXCL12	N-Cadherin^+ cells in the endosteum of the trabecular bone region^Citation42	Preserve reserve HSCs^Citation43 Maintain functional HSCs^Citation43 Support hematopoietic regeneration post-myeloablation^Citation43
EC	SCF CXCL12 PTN^Citation31 E-/P-selectin ANGPTL2^Citation44	CD31^+VE-Cadherin^+VEGFR1^+VEGFR2^+ cells^Citation45	Maintain HSCs^Citation20 HSCs regeneration^Citation31 HSCs homing and engraftment^Citation46 Localization and specification of HSCs^Citation1 HSC stemness maintenance^Citation44
Osteoblasts	OPN G-CSF	Alkaline phosphatase^+, osteocalcin^+ and CD10^+ bone-lining endosteal cells^Citation47	Negatively regulates HSC frequency^Citation48 Mediate HSC migration in and out of the BM^Citation49
Adipocytes	Adiponectin	Perilipin^+ and Oil RedO^+ cells, present throughout the bone marrow^Citation26	Sustain HSC survival^Citation27 HSCs regeneration^Citation28 Negative regulation of hematopoietic recovery^Citation26,Citation50 and HSCs expansion^Citation25
Megakaryocytes	TPO TGF-β1 CXCL4	CD41^+ cells, closely associated with sinusoids^Citation51	Maintenance of HSCs quiescence and promotion of HSC regeneration under stress condition^Citation52,Citation53 HSCs differentiation^Citation54 Replenish hematopoietic cells^Citation55
Macrophages	TNF-α	CD45^+F4/80^+ cells and marked by Csf1r-GFP	Regulate erythropoiesis^Citation56
Regulatory T cells	IL-10	CD4^+CD25^+FOXP3^+ cells	Regulate lympho-hematopoiesis^Citation57 Maintain HSCs and promote allo-HSCs engraftment^Citation58
Schwann cells	Integrin-β8	Myelinating Schwann cells express MBP and non-myelinating Schwann cells express GFAP	Maintenance of HSC hibernation^Citation59,Citation60
SNS nerves	Noradrenaline Neuropeptide Y^Citation61	Synapsed on perivascular cells	HSPCs mobilization^Citation62 HSCs regeneration^Citation61 HSCs hibernation^Citation61

Various cell types have been implicated in regulating hematopoietic stem cell (HSC) activity. They contribute to HSC regulation indirectly or directly by synthesizing niche factors in the form of cell-bound or secreted molecules.

HSCs, hematopoietic stem cells; LepR+ stromal cells, leptin-receptor-expressing stromal cells; SCF, stem cell factor; PTN, pleiotrophin; CXCL12, CXC-chemokine ligand 12; Nes-GFP+ stromal cells, Nestin-expressing-GFP+ stromal cells; CAR cells, CXCL12 abundant reticular cells; IL-6, interleukin-6; EC, endothelial cells; ANGPTL2, angiopoietin-like proteins 2; VEGFR, vascular endothelial growth factor receptor; OPN, osteopontin; G-CSF, granulocyte-colony stimulating factor; TPO, thrombopoietin; TGF-β1, transforming growth factor-β1; CXCL4, CXC-chemokine ligand 4; TNF-α, tumor necrosis factor-α; MBP, myelin basic protein; GFAP, glial fibrillary acidic protein; SNS, sympathetic nervous system.

Figure 2. Toll-like receptor signaling in HSCs proliferation and differentiation.

TLR1, TLR2, TLR4, TLR5, TLR6 and TLR11 are located on the cell surface, while TLR3, TLR7, TLR8 and TLR9 are located in the endosome/lysosome. TLR activation initiates a MyD88/TRIF-dependent signaling cascade, which can activate NF-κB and IRF, resulting in the proliferation and biased-differentiation of HSC.

HSCs, hematopoietic stem cells; TLR, Toll-like receptors; IRF, interferon-regulatory factors; PAMPs, Pathogen-associated molecular patterns.

Figure 3. Modulation of HSCs function by SCFAs.

HSCs, hematopoietic stem cells; SCFAs, short-chain fatty acids; LepR⁺ MSC, leptin-receptor-expressing mesenchymal stem cells; SCF, stem cell factor; SDF1, stromal cell derived factor 1.

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