How is blood (re-)made? Regeneration of human hematopoietic stem cells after transplantation

Descripción del proyecto

Estudio de la regeneración de las células hematopoyéticas humanas tras un trasplante

Comprender cómo las células madre y progenitoras hematopoyéticas (CMPH) regeneran la sangre es fundamental para mejorar las terapias de trasplante de células madre hematopoyéticas (TCMH). Estas intervenciones presentan una elevada tasa anual de mortalidad por complicaciones, lo que urge a desarrollar estrategias predictivas más eficaces. En el proyecto RESTART, financiado por el Consejo Europeo de Investigación, se estudiará la regeneración hematopoyética en seres humanos analizando miles de CMPH y células nicho de la médula ósea. La investigación se llevará a cabo en el mayor centro oncológico pediátrico de Europa y, en ella, se analizarán muestras de médula ósea de niños receptores de un CMH, así como de los donantes, antes y después del trasplante. El objetivo del proyecto es identificar los estados celulares que predicen resultados adversos del TCMH, lo cual podría contribuir a mejorar la tasa de supervivencia y la comprensión de la regeneración tisular.

Objetivo

How hematopoietic stem and progenitor cells (HSPCs) regenerate blood is a major unsolved question, frustrating their effective use for therapy. Every year, >40.000 patients receive an HSPC transplantation (HSCT), as a last-resort therapy for various diseases, including leukemia. However, ~40% of HSCT recipients die, due to poor outgrowth of the donor HSPCs, inflammatory complications or relapse. There is an unmet need for strategies to predict and prevent these adverse outcomes. In mice, single-cell methods have revolutionized our understanding of how hematopoiesis is organized, allowing us to control the outcome of murine HSCT in detail. In contrast, our understanding of human hematopoietic regeneration, and our ability to control this process, is lagging behind. As a clinician in pediatric HSCT and stem cell biologist, my mission is to change this. RESTART aims to comprehensively characterize the cellular and molecular mechanisms guiding hematopoietic regeneration in humans. I have pioneered single-cell methods to study human HSPC biology. Here, we will apply state-of-the-art multiomics to dissect the identities and functional states of thousands of HSPCs and their surrounding niche cells in human bone marrow (BM). Embedded in Europe’s largest pediatric cancer center, we will apply these methods to a unique, longitudinal collection of BM samples of pediatric HSCT recipients and their donors, collected before and up to a year after HSCT. Our objectives are: (1) Dissect the cellular and molecular composition of the HSPC population during successful hematopoietic regeneration in human HSCT recipients; (2) Determine how HSCT-induced alterations in BM niche cells affect HSPC fate; (3) Leverage this information to identify and validate single-cell states or trajectories predictive of adverse HSCT outcome (graft failure, relapse). This study will contribute to improved survival of human HSCT recipients and to increased fundamental knowledge on human tissue regeneration.