Mesenchymal and haematopoietic stem cells form a unique bone marrow niche.
The cellular constituents forming the haematopoietic stem cell (HSC) niche in the bone marrow are unclear, with studies implicating osteoblasts, endothelial and perivascular cells. Here we demonstrate that mesenchymal stem cells (MSCs), identified using nestin expression, constitute an essential HSC niche component. Nestin(+) MSCs contain all the bone-marrow colony-forming-unit fibroblastic activity and can be propagated as non-adherent 'mesenspheres' that can self-renew and expand in serial transplantations. Nestin(+) MSCs are spatially associated with HSCs and adrenergic nerve fibres, and highly express HSC maintenance genes. These genes, and others triggering osteoblastic differentiation, are selectively downregulated during enforced HSC mobilization or beta3 adrenoreceptor activation. Whereas parathormone administration doubles the number of bone marrow nestin(+) cells and favours their osteoblastic differentiation, in vivo nestin(+) cell depletion rapidly reduces HSC content in the bone marrow. Purified HSCs home near nestin(+) MSCs in the bone marrow of lethally irradiated mice, whereas in vivo nestin(+) cell depletion significantly reduces bone marrow homing of haematopoietic progenitors. These results uncover an unprecedented partnership between two distinct somatic stem-cell types and are indicative of a unique niche in the bone marrow made of heterotypic stem-cell pairs.
Méndez-Ferrer
Simón
S
Department of Medicine, Mount Sinai School of Medicine, New York, New York 10029, USA. simon.mendez-ferrer@cnic.es
Michurina
Tatyana V
TV
Ferraro
Francesca
F
Mazloom
Amin R
AR
Macarthur
Ben D
BD
Lira
Sergio A
SA
Scadden
David T
DT
Ma'ayan
Avi
A
Enikolopov
Grigori N
GN
Frenette
Paul S
PS
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division; D019070:Cell Lineage / Q000187:drug effects; D002465:Cell Movement; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000378:metabolism; D019902:Chondrocytes / Q000166:cytology / Q000187:drug effects; D005786:Gene Expression Regulation / Q000235:genetics; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D007381:Intermediate Filament Proteins / Q000378:metabolism; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D039902:Multipotent Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D064231:Nestin; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010281:Parathyroid Hormone / Q000494:pharmacology; D055153:Stem Cell Niche / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D017154:Stromal Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D013564:Sympathetic Nervous System / Q000502:physiology
D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D007381:Intermediate Filament Proteins; D009419:Nerve Tissue Proteins; C577485:Nes protein, mouse; D064231:Nestin; D010281:Parathyroid Hormone; D016179:Granulocyte Colony-Stimulating Factor