Inhibiting stromal cell heparan sulfate synthesis improves stem cell mobilization and enables engraftment without cytotoxic conditioning
Year: 2014
Type: article
Abstract: The glycosyltransferase gene, Ext1, is essential for heparan sulfate production. Induced deletion of Ext1 selectively in Mx1-expressing bone marrow (BM) stromal cells, a known population of skeletal stem/progenitor cells, in adult mice resulted in marked changes in hematopoietic stem and progenitor cell (HSPC) localization. HSPC egressed from BM to spleen after Ext1 deletion. This was associated with altered signaling in the stromal cells and with reduced vascular cell adhesion molecule 1 production by them. Further, pharmacologic inhibition of heparan sulfate mobilized qualitatively more potent and quantitatively more HSPC from the BM than granulocyte colony-stimulating factor alone, including in a setting of granulocyte colony-stimulating factor resistance. The reduced presence of endogenous HSPC after Ext1 deletion was associated with engraftment of transfused HSPC without any toxic conditioning of the host. Therefore, inhibiting heparan sulfate production may provide a means for avoiding the toxicities of radiation or chemotherapy in HSPC transplantation for nonmalignant conditions.
Source: Blood
Authors: Borja Saez, Francesca Ferraro, Rushdia Z. Yusuf, Colleen M. Cook, Vionnie W. C. Yu, Ana Pardo-Saganta, Stephen M. Sykes, Rahul Palchaudhuri, Amir Schajnovitz, Sutada Lotinun, Stefania Lymperi, Simon Mendez-Ferrer, Raquel del Toro, Robyn Day, Radovan Vasic, Sanket S. Acharya, Roland Baron, Charles P. Lin, Yu Yamaguchi, Amy J. Wagers, David T. Scadden
Institutions: Harvard University, Massachusetts General Hospital, Harvard Stem Cell Institute, Fox Chase Cancer Center, Spanish National Centre for Cardiovascular Research, Center for Systems Biology, Sanford Burnham Prebys Medical Discovery Institute, Joslin Diabetes Center, Howard Hughes Medical Institute
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: Microenvironmental control of progenitors in organ dysfunction and repair, Mechanisms of Hematopoiesis in AIDS, G1721448, Heparan Sulfate in Skeletal Development and Diseases, Progenitor Cell Biology Consortium Administrative Coordinating Center, Stem Cell Engagement of the Niche, Foxo transcription factors are required for maintenance of acute myeloid leukemia, G7186816333, G7387359766, G7792392908, G8137996916, Direct visualization and characterization of hypoxia in the bone marrow
OpenAlex ID: W2031473795