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GPRASP proteins are critical negative regulators of hematopoietic stem cell transplantation.

ABSTRACT: Hematopoietic stem cell (HSC) transplantation (HSCT) is often exploited to treat hematologic disease. Donor HSCs must survive, proliferate, and differentiate in the damaged environment of the reconstituting niche. Illuminating molecular mechanisms regulating the activity of transplanted HSCs will inform efforts to improve HSCT. Here, we report that G-protein-coupled receptor-associated sorting proteins (GPRASPs) function as negative regulators of HSCT. Silencing of Gprasp1 or Gprasp2 increased the survival, quiescence, migration, niche retention, and hematopoietic repopulating activity of hematopoietic stem and progenitor cells (HSPCs) posttransplant. We further show that GPRASP1 and GPRASP2 promote the degradation of CXCR4, a master regulator of HSC function during transplantation. CXCR4 accumulates in Gprasp-deficient HSPCs, boosting their function posttransplant. Thus, GPRASPs negatively regulate CXCR4 stability in HSCs. Our work reveals GPRASP proteins as negative regulators of HSCT and CXCR4 activity. Disruption of GPRASP/CXCR4 interactions could be exploited in the future to enhance the efficiency of HSCT.

SUBMITTER: Morales-Hernandez A

PROVIDER: S-EPMC7118811 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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GPRASP proteins are critical negative regulators of hematopoietic stem cell transplantation.

Morales-Hernández Antonio A Benaksas Chaïma C Chabot Ashley A Caprio Claire C Ferdous Maheen M Zhao Xiwen X Kang Guolian G McKinney-Freeman Shannon S

Blood 20200401 14

Hematopoietic stem cell (HSC) transplantation (HSCT) is often exploited to treat hematologic disease. Donor HSCs must survive, proliferate, and differentiate in the damaged environment of the reconstituting niche. Illuminating molecular mechanisms regulating the activity of transplanted HSCs will inform efforts to improve HSCT. Here, we report that G-protein-coupled receptor-associated sorting proteins (GPRASPs) function as negative regulators of HSCT. Silencing of Gprasp1 or Gprasp2 increased t ...[more]

PMID: 32027737

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Project description:ContextHematopoietic stem cell transplantation (HSCT) requires significant infrastructure. Little is known about HSCT use and the factors associated with it on a global level.ObjectivesTo determine current use of HSCT to assess differences in its application and to explore associations of macroeconomic factors with transplant rates on a global level.Design, setting, and patientsRetrospective survey study of patients receiving allogeneic and autologous HSCTs for 2006 collected by 1327 centers in 71 participating countries of the Worldwide Network for Blood and Marrow Transplantation. The regional areas used herein are (1) the Americas (the corresponding World Health Organization regions are North and South America); (2) Asia (Southeast Asia and the Western Pacific Region, which includes Australia and New Zealand); (3) Europe (includes Turkey and Israel); and (4) the Eastern Mediterranean and Africa.Main outcome measuresTransplant rates (number of HSCTs per 10 million inhabitants) by indication, donor type, and country; description of main differences in HSCT use; and macroeconomic factors of reporting countries associated with HSCT rates.ResultsThere were 50 417 first HSCTs; 21 516 allogeneic (43%) and 28 901 autologous (57%). The median HSCT rates varied between regions and countries from 48.5 (range, 2.5-505.4) in the Americas, 184 (range, 0.6-488.5) in Asia, 268.9 (range, 5.7-792.1) in Europe, and 47.7 (range, 2.8-95.3) in the Eastern Mediterranean and Africa. No HSCTs were performed in countries with less than 300,000 inhabitants, smaller than 960 km(2), or having less than US $680 gross national income per capita. Use of allogeneic or autologous HSCT, unrelated or family donors for allogeneic HSCT, and proportions of disease indications varied significantly between countries and regions. In linear regression analyses, government health care expenditures (r(2) = 77.33), HSCT team density (indicates the number of transplant teams per 1 million inhabitants; r(2) = 76.28), human development index (r(2) = 74.36), and gross national income per capita (r(2) = 74.04) showed the highest associations with HSCT rates.ConclusionHematopoietic stem cell transplantation is used for a broad spectrum of indications worldwide, but most frequently in countries with higher gross national incomes, higher governmental health care expenditures, and higher team densities.

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GPRASP proteins are critical negative regulators of hematopoietic stem cell transplantation.

Publications

GPRASP proteins are critical negative regulators of hematopoietic stem cell transplantation.

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