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Hematopoiesis
Natural estrogens enhance the engraftment of human hematopoietic stem and progenitor cells in immunodeficient mice
Ferrata Storti Foundation
Haematologica 2021 Volume 106(6):1659-1670
Sara Fañanas-Baquero,1,2 Israel Orman,1,2 Federico Becerra Aparicio,1,2 Silvia Bermudez de Miguel,1,2 Jordi Garcia Merino,1,2 Rosa Yañez,1,2 Yolanda Fernandez Sainz,1,2 Rebeca Sánchez,1,2 Mercedes Dessy-Rodríguez,1,2 Omaira Alberquilla,1,2 David Alfaro,3 Agustin Zapata,3 Juan A. Bueren,1,2 Jose Carlos Segovia1,2 and Oscar Quintana-Bustamante1,2
1Hematopoietic Innovative Therapies Division, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT) and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER); 2Unidad Mixta de Terapias Avanzadas, Instituto de Investigación Sanitaria Fundación Jiménez Díaz and 3Department of Cell Biology, Faculty of Biology, Complutense University of Madrid, Madrid, Spain.
ABSTRACT
Hematopoietic stem and progenitor cells (HSPC) are crucial in the maintenance of lifelong production of all blood cells. These stem cells are highly regulated to maintain homeostasis through a delicate balance between quiescence, self-renewal and differentiation. However, this balance is altered during the recovery after HSPC transplantation. Transplantation efficacy can be limited by inadequate hematopoietic stem cell number, poor homing, low level of engraftment, or limited self-renewal. As recent evidence indicates that estrogens are involved in regulating hematopoiesis, we sought to examine whether natural estrogens (estrone or E1, estradiol or E2, estriol or E3 and estetrol or E4) modulate human HSPC. Our results show that human HSPC subsets express estrogen receptors, and that signaling is activated by E2 and E4 on these cells. Additionally, these natural estrogens cause different effects on human progenitors in vitro. We found that both E2 and E4 expand human HSPC. However, E4 was the best tolerated estrogen and promoted cell cycling of human hematopoietic pro- genitors. Furthermore, we found that E2 and, more significantly, E4 doubled human hematopoietic engraftment in immunodeficient mice without alter- ing other HSPC properties. Finally, the impact of E4 on promoting human hematopoietic engraftment in immunodeficient mice might be mediated through the regulation of mesenchymal stromal cells in the bone marrow niche. Collectively, our data demonstrate that E4 is well tolerated and enhances human reconstitution in immunodeficient mice directly, by mod- ulating human hematopoietic progenitor properties, and indirectly, by inter- acting with the bone marrow niche. This might have particular relevance for improving hematopoietic recovery after myeloablative conditioning, espe- cially when limited numbers of HSPC are available.
Introduction
Hematopoietic stem cells (HSC) are a rare cell population resident in the bone mar- row (BM) of adult mammals and are at the top of a hierarchy of progenitors that become progressively restricted to several or a single blood lineage. HSC are capable of self-renewal and multipotent differentiation to all blood cell lineages,1 and are cru- cial for the maintenance of lifelong production of all blood cells. They are homeosta- tically regulated through a delicate balance between quiescence, self-renewal and dif- ferentiation. Although HSC divide infrequently, they are activated to proliferate in response to BM injury to re-establish homeostasis.2 Transplantation of hematopoietic stem and progenitor cells (HSPC) is routinely used to reconstitute hematopoiesis after myeloablative regimens to treat leukemia or hematopoietic genetic diseases. However, the efficacy of HSPC transplantation can be limited by inadequate cell
Correspondence:
OSCAR QUINTANA-BUSTAMANTE
oscar.quintana@ciemat.es
JOSE CARLOS SEGOVIA jc.segovia@ciemat.es
Received: August 2, 2019. Accepted: April 28, 2020. Pre-published: April 30, 2020.
https://doi.org/10.3324/haematol.2019.233924
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