Cytohesin 1 regulates homing and engraftment of human hematopoietic stem and progenitor cells

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Cytohesin 1 regulates homing and engraftment of human hematopoietic stem and progenitor cells. / Rak, Justyna; Foster, Katie; Potrzebowska, Kasia; Safaee Talkhoncheh, Mehrnaz; Miharada, Natsumi; Komorowska, Karolina; Torngren, Therese; Kvist, Anders; Borg, Åke; Svensson, Lena; Bonnet, Dominique; Larsson, Jonas.

In: Blood, Vol. 129, No. 8, 23.02.2017, p. 950-958.

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TY - JOUR

T1 - Cytohesin 1 regulates homing and engraftment of human hematopoietic stem and progenitor cells

AU - Rak, Justyna

AU - Foster, Katie

AU - Potrzebowska, Kasia

AU - Safaee Talkhoncheh, Mehrnaz

AU - Miharada, Natsumi

AU - Komorowska, Karolina

AU - Torngren, Therese

AU - Kvist, Anders

AU - Borg, Åke

AU - Svensson, Lena

AU - Bonnet, Dominique

AU - Larsson, Jonas

PY - 2017/2/23

Y1 - 2017/2/23

N2 - Adhesion is a key component of hematopoietic stem cell regulation mediating homing and retention to the niche in the bone marrow. Here, using an RNA interference screen, we identify cytohesin 1 (CYTH1) as a critical mediator of adhesive properties in primary human cord blood-derived hematopoietic stem and progenitor cells (HSPCs). Knockdown of CYTH1 disrupted adhesion of HSPCs to primary human mesenchymal stroma cells. Attachment to fibronectin and ICAM1, 2 integrin ligands, was severely impaired, and CYTH1-deficient cells showed a reduced integrin b1 activation response, suggesting that CYTH1 mediates integrin-dependent functions. Transplantation of CYTH1-knockdown cells to immunodeficient mice resulted in significantly lower long-term engraftment levels, associated with a reduced capacity of the transplanted cells to home to the bone marrow. Intravital microscopy showed that CYTH1 deficiency profoundly affects HSPC mobility and localization within the marrow space and thereby impairs proper lodgment into the niche. Thus, CYTH1 is a novel major regulator of adhesion and engraftment in human HSPCs through mechanisms that, at least in part, involve the activation of integrins.

AB - Adhesion is a key component of hematopoietic stem cell regulation mediating homing and retention to the niche in the bone marrow. Here, using an RNA interference screen, we identify cytohesin 1 (CYTH1) as a critical mediator of adhesive properties in primary human cord blood-derived hematopoietic stem and progenitor cells (HSPCs). Knockdown of CYTH1 disrupted adhesion of HSPCs to primary human mesenchymal stroma cells. Attachment to fibronectin and ICAM1, 2 integrin ligands, was severely impaired, and CYTH1-deficient cells showed a reduced integrin b1 activation response, suggesting that CYTH1 mediates integrin-dependent functions. Transplantation of CYTH1-knockdown cells to immunodeficient mice resulted in significantly lower long-term engraftment levels, associated with a reduced capacity of the transplanted cells to home to the bone marrow. Intravital microscopy showed that CYTH1 deficiency profoundly affects HSPC mobility and localization within the marrow space and thereby impairs proper lodgment into the niche. Thus, CYTH1 is a novel major regulator of adhesion and engraftment in human HSPCs through mechanisms that, at least in part, involve the activation of integrins.

UR - http://www.scopus.com/inward/record.url?scp=85014938728&partnerID=8YFLogxK

U2 - 10.1182/blood-2016-06-720649

DO - 10.1182/blood-2016-06-720649

M3 - Article

VL - 129

SP - 950

EP - 958

JO - Blood

T2 - Blood

JF - Blood

SN - 1528-0020

IS - 8

ER -