Inhibiting stromal cell heparan sulfate synthesis improves stem cell mobilization and enables engraftment without cytotoxic conditioning

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

doi:10.1182/blood-2014-08-593426

Inhibiting stromal cell heparan sulfate synthesis improves stem cell mobilization and enables engraftment without cytotoxic conditioning

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. WagersDavid T. Scadden

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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 inhematopoieticstemandprogenitorcell(HSPC)localization. HSPCegressedfromBMto 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. (Blood.

Original language	English
Pages (from-to)	2937-2947
Number of pages	11
Journal	Blood
Volume	124
Issue number	19
DOIs	https://doi.org/10.1182/blood-2014-08-593426
State	Published - Nov 6 2014

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Saez, B., Ferraro, F., Yusuf, R. Z., Cook, C. M., Yu, V. W. C., Pardo-Saganta, A., Sykes, S. M., Palchaudhuri, R., Schajnovitz, A., Lotinun, S., Lymperi, S., Mendez-Ferrer, S., Del Toro, R., Day, R., Vasic, R., Acharya, S. S., Baron, R., Lin, C. P., Yamaguchi, Y., ... Scadden, D. T. (2014). Inhibiting stromal cell heparan sulfate synthesis improves stem cell mobilization and enables engraftment without cytotoxic conditioning. Blood, 124(19), 2937-2947. https://doi.org/10.1182/blood-2014-08-593426

@article{ac3199ab3c544bfaac87ebfcf3811158,

title = "Inhibiting stromal cell heparan sulfate synthesis improves stem cell mobilization and enables engraftment without cytotoxic conditioning",

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 inhematopoieticstemandprogenitorcell(HSPC)localization. HSPCegressedfromBMto 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. (Blood.",

author = "Borja Saez and Francesca Ferraro and Yusuf, {Rushdia Z.} and Cook, {Colleen M.} and Yu, {Vionnie W.C.} and Ana Pardo-Saganta and Sykes, {Stephen M.} and Rahul Palchaudhuri and Amir Schajnovitz and Sutada Lotinun and Stefania Lymperi and Simon Mendez-Ferrer and {Del Toro}, Raquel and Robyn Day and Radovan Vasic and Acharya, {Sanket S.} and Roland Baron and Lin, {Charles P.} and Yu Yamaguchi and Wagers, {Amy J.} and Scadden, {David T.}",

note = "Publisher Copyright: {\textcopyright} 2014 by The American Society of Hematology.",

year = "2014",

month = nov,

day = "6",

doi = "10.1182/blood-2014-08-593426",

language = "English",

volume = "124",

pages = "2937--2947",

journal = "Blood",

issn = "0006-4971",

number = "19",

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Saez, B, Ferraro, F, Yusuf, RZ, Cook, CM, Yu, VWC, Pardo-Saganta, A, Sykes, SM, Palchaudhuri, R, Schajnovitz, A, Lotinun, S, Lymperi, S, Mendez-Ferrer, S, Del Toro, R, Day, R, Vasic, R, Acharya, SS, Baron, R, Lin, CP, Yamaguchi, Y, Wagers, AJ & Scadden, DT 2014, 'Inhibiting stromal cell heparan sulfate synthesis improves stem cell mobilization and enables engraftment without cytotoxic conditioning', Blood, vol. 124, no. 19, pp. 2937-2947. https://doi.org/10.1182/blood-2014-08-593426

TY - JOUR

T1 - Inhibiting stromal cell heparan sulfate synthesis improves stem cell mobilization and enables engraftment without cytotoxic conditioning

AU - Saez, Borja

AU - Ferraro, Francesca

AU - Yusuf, Rushdia Z.

AU - Cook, Colleen M.

AU - Yu, Vionnie W.C.

AU - Pardo-Saganta, Ana

AU - Sykes, Stephen M.

AU - Palchaudhuri, Rahul

AU - Schajnovitz, Amir

AU - Lotinun, Sutada

AU - Lymperi, Stefania

AU - Mendez-Ferrer, Simon

AU - Del Toro, Raquel

AU - Day, Robyn

AU - Vasic, Radovan

AU - Acharya, Sanket S.

AU - Baron, Roland

AU - Lin, Charles P.

AU - Yamaguchi, Yu

AU - Wagers, Amy J.

AU - Scadden, David T.

PY - 2014/11/6

Y1 - 2014/11/6

N2 - 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 inhematopoieticstemandprogenitorcell(HSPC)localization. HSPCegressedfromBMto 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. (Blood.

AB - 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 inhematopoieticstemandprogenitorcell(HSPC)localization. HSPCegressedfromBMto 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. (Blood.

UR - http://www.scopus.com/inward/record.url?scp=84909608192&partnerID=8YFLogxK

U2 - 10.1182/blood-2014-08-593426

DO - 10.1182/blood-2014-08-593426

M3 - Article

C2 - 25202142

AN - SCOPUS:84909608192

SN - 0006-4971

VL - 124

SP - 2937

EP - 2947

JO - Blood

JF - Blood

IS - 19

ER -

Inhibiting stromal cell heparan sulfate synthesis improves stem cell mobilization and enables engraftment without cytotoxic conditioning

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