Phenotypically identical hemopoietic stem cells isolated from different regions of bone marrow have different biologic potential

Grassinger, Jochen; Haylock, David N.; Williams, Brenda; Olsen, Gemma Haines; Nilsson, Susan K.

doi:10.1182/blood-2009-12-260703

Cited by 98 publications

(93 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We next characterized the nature of aging‐associated changes in stroma (Köhler et al , 2009; Grassinger et al , 2010). Cells that are located < 10 cell diameters to the bone are enriched for stroma cells from the endosteal region of the bone referred to as the endosteal niche and were detached for our experiments by collagenase treatment (Fig 2Ai–iii).…”

Section: Resultsmentioning

confidence: 99%

Osteopontin attenuates aging‐associated phenotypes of hematopoietic stem cells

et al. 2017

View full text Add to dashboard Cite

Upon aging, hematopoietic stem cells (HSCs) undergo changes in function and structure, including skewing to myeloid lineages, lower reconstitution potential and loss of protein polarity. While stem cell intrinsic mechanisms are known to contribute to HSC aging, little is known on whether age‐related changes in the bone marrow niche regulate HSC aging. Upon aging, the expression of osteopontin (OPN) in the murine bone marrow stroma is reduced. Exposure of young HSCs to an OPN knockout niche results in a decrease in engraftment, an increase in long‐term HSC frequency and loss of stem cell polarity. Exposure of aged HSCs to thrombin‐cleaved OPN attenuates aging of old HSCs, resulting in increased engraftment, decreased HSC frequency, increased stem cell polarity and a restored balance of lymphoid and myeloid cells in peripheral blood. Thus, our data suggest a critical role for reduced stroma‐derived OPN for HSC aging and identify thrombin‐cleaved OPN as a novel niche informed therapeutic approach for ameliorating HSC phenotypes associated with aging.

show abstract

Section: Resultsmentioning

confidence: 99%

Osteopontin attenuates aging‐associated phenotypes of hematopoietic stem cells

et al. 2017

View full text Add to dashboard Cite

show abstract

“…Functional analysis of BM HSC demonstrate those with the greatest hematopoietic potential, which preferentially localize in the endosteal region (B12 cell diameters from the bone surface 13 ). Of note, HSC identical for the classic Lin À Sca-1 þ ckit þ CD150 þ CD48 À phenotype, but isolated from endosteal BM have greater homing potential and enhanced long-term, multi-lineage hematopoietic reconstitution relative to HSC isolated from the central medullary cavity 14 . Thus, the therapeutic targeting of endosteal HSC for mobilization should provide better transplant outcomes.…”

mentioning

confidence: 99%

Therapeutic targeting and rapid mobilization of endosteal HSC using a small molecule integrin antagonist

Cao

Zhang

Grassinger

et al. 2016

Experimental Hematology

Self Cite

View full text Add to dashboard Cite

The inherent disadvantages of using granulocyte colony-stimulating factor (G-CSF) for hematopoietic stem cell (HSC) mobilization have driven efforts to identify alternate strategies based on single doses of small molecules. Here, we show targeting a 9 b 1 /a 4 b 1 integrins with a single dose of a small molecule antagonist (BOP (N-(benzenesulfonyl)-L-prolyl-L-O-(1-pyrrolidinylcarbonyl)tyrosine)) rapidly mobilizes long-term multi-lineage reconstituting HSC. Synergistic engraftment augmentation is observed when BOP is co-administered with AMD3100. Impressively, HSC in equal volumes of peripheral blood (PB) mobilized with this combination effectively out-competes PB mobilized with G-CSF. The enhanced mobilization observed using BOP and AMD3100 is recapitulated in a humanized NODSCIDIL2Rg À / À model, demonstrated by a significant increase in PB CD34 þ cells. Using a related fluorescent analogue of BOP (R-BC154), we show that this class of antagonists preferentially bind human and mouse HSC and progenitors via endogenously primed/activated a 9 b 1 /a 4 b 1 within the endosteal niche. These results support using dual a 9 b 1 /a 4 b 1 inhibitors as effective, rapid and transient mobilization agents with promising clinical applications.

show abstract

“…Of note, inhibition of α 9 β 1 was identified to be important for HSC mobilization, while α 4 β 1 was predominantly involved in WBC mobilization [87]. Using a fluorescent analogue of BOP termed "R-BC154" [88], human and murine HSC were found to bind BOP through endogenously primed/ activated integrins within the endosteal BM, the region near bone where HSC with superior homing potential and enhanced proliferative capacity reside [89]. These observations are consistent with the greater amount of divalent metal cations (Mn 2+ , Mg 2+ and Ca…”

Section: Integrin Antagonistsmentioning

confidence: 99%