Investigating enhancement of engraftment potential in human hematopoietic stem cells

The National Institutes of Health National Heart Lung and Blood Institute awarded Trustees of Boston University $100,228 on December 12, 2026, under the Cardiovascular Diseases Research program (CFDA 93.837) to investigate enhancement of engraftment potential in human hematopoietic stem cells. The research addresses the challenge of preserving hematopoietic stem cell functionality during the ex vivo culture steps required for gene editing therapies. The project employs multi-modal profiling of fetal liver hematopoietic stem and progenitor cells to decipher molecular signals and factors characteristic of highly engraftable stem cells, with findings intended to guide advances in ex vivo culture conditions that sustain stem cell function and improve the success of hematopoietic stem cell transplantations for hematological and immune disorders. Performance occurs in Roxbury, Massachusetts, with a period of performance through June 15, 2029.

Abstract

Hematopoietic stem cell transplantations (hscts) are curative therapies for a range of debilitating hematological and immune disorders. This approach relies on the ability of healthy donor hematopoietic stem cells (hscs) to engraft within a recipient and subsequently contribute to long term multilineage hematopoiesis, effectively replacing the diseased blood system with a healthy one. The demand for hscts is expected to rise, as newly approved FDA gene editing therapies are now being offered for the treatment of a variety of blood- borne diseases offering patients the opportunity to be treated with their own genetically modified hscs. Although promising, a significant challenge with this approach lies in the EX vivo culture step required for gene editing. Removal of hscs from their niche environment and associated culturing leads to a loss of stem cell functionality, ultimately compromising their engraftment potential. To improve the success of hscts, IT is imperative that HSC culture systems evolve to preserve stem cell functionality. To decipher the underlying signals and factors supportive and characteristic to highly engraftable hscs, we look to the fetal liver (FL), a developmental hub for newly emerged hscs. Notably, FL hscs, exhibit superior engraftment capacity compared to hscs at other developmental timepoints. This observation leads US to hypothesize that the FL is uniquely equipped to support highly engraftable hscs, and unraveling the underlying signals, factors, and interactions characteristic to these cells and their microenvironments will guide advances in EX vivo culture conditions that are tailored to sustain HSC function. Our previous multi-modal profiling of FL hematopoietic stem and progenitor cells (hspcs) revealed a molecular signature characteristic to the most functional FL hscs. Within this signature we noted enrichment of ID1-3, a class of factors known to be implicated in safeguarding the balance between quiescence and replication. We plan to supplement hspc EX vivo culture systems with biologically relevant ID gene modulators, characterize subsequent changes in engraftment potential, and investigate the mechanistic implication of this modulation. To comprehensively characterize the FL HSC niche, we will integrate xenium in situ spatial transcriptomic analysis with immunofluorescence staining to identify highly engraftable hscs and their surrounding cellular environment. This approach will allow for US to pinpoint candidate factors involved in preserving engraftment potential. Our FL guided approach will facilitate advances in EX vivo systems that support or even enhance the engraftment potential, thereby improving the safety and success of hscts. This project will be conducted at the center for regenerative medicine (crem) at the boston university school of medicine, under the mentorship of DRS. KIM vanuytsel, ruben dries, and george murphy, whose expertise spans hematology, spatial biology, and regenerative medicine. Through this work, i will receive interdisciplinary training that will prepare me for a successful career as an independent research scientist.