Research, Desai Lab

We study hematopoietic stem cells (HSCs), the rare bone marrow cells responsible for producing every type of blood cell in the body. Despite their small numbers, HSCs sustain the entire blood system across a lifetime, continuously self-renewing while giving rise to red cells, white cells, and platelets. Understanding how they accomplish this, and how that capacity breaks down with age, injury, or disease, is the central question driving our work.

HSCs don't function in isolation. They live in a specialized bone marrow microenvironment called the niche, where signals from neighboring cells govern their behavior. When the niche is disrupted, HSC function deteriorates, contributing to blood disorders, bone marrow failure, and hematologic malignancies. We study these interactions using mouse models and in vitro systems, examining how HSC behavior shifts under stress, during aging, and after transplantation.

A major thread running through the lab is 15-PGDH, an enzyme we have shown plays a significant role in hematopoietic regeneration. Inhibiting it can protect against immune-mediated bone marrow failure, activate the splenic niche to support recovery, and improve HSC function in aging animals. Beyond 15-PGDH, we are investigating sex-specific differences in blood production and HSC biology, screening FDA-approved drugs for their potential to improve bone marrow transplant outcomes, and exploring how neurodegenerative disease affects hematopoietic function.

15-PGDH inhibition for hematopoietic recovery

We are investigating how inhibiting the enzyme 15-PGDH (15-hydroxyprostaglandin dehydrogenase) can boost hematopoietic regeneration following stress or during aging. Prior work from the lab demonstrated that 15-PGDH inhibition protects against immune-mediated bone marrow failure and activates the splenic niche to support recovery.

Current work aims to translate these findings into improved strategies for bone marrow transplantation and treatment of aplastic anemia. We are also examining the molecular mechanisms through which 15-PGDH shapes HSC behavior across different physiological and pathological contexts, including aging.

Sexual dimorphism in hematopoiesis

We explore the differences between male and female hematopoiesis to understand how sex-specific factors influence blood cell production and HSC function. Our 2024 publication demonstrated that female HSCs display a more quiescent and less inflammatory profile, while males exhibit a proliferative advantage, with distinct biological pathways shaping both steady-state and regenerative hematopoiesis.

This work has direct implications for personalized approaches to bone marrow transplantation. By understanding how sex shapes the biology of the donor and recipient HSC niche, we aim to improve transplant matching strategies and post-transplant outcomes.

Repurposing FDA-approved drugs to enhance hematopoietic function

We aim to identify existing FDA-approved therapeutics that can be repurposed to enhance hematopoietic function and improve recovery after bone marrow transplantation. This project leverages our mechanistic understanding of the HSC niche to rapidly identify candidates with clinical translation potential.

By focusing on drugs already approved for human use, we can shorten the path from discovery to clinical application. Candidates are validated in relevant mouse models and assessed for their effects on HSC engraftment, expansion, and long-term function.

Selective XPO1 inhibition in inflammatory disease

XPO1 regulates hematopoietic stem cell output and T cell activation, but existing inhibitors like selinexor carry significant toxicity. Working with Drew Adams' lab at CWRU, we are studying a new class of compounds called SITAs (selective inhibitors of transcriptional activation) that selectively block XPO1's role at chromatin without broadly disrupting nuclear export.

We have shown that SITAs improve survival in a mouse model of graft-versus-host disease (GVHD) while preserving normal blood cell counts, a meaningful improvement over existing approaches. We are now exploring their therapeutic potential across GVHD and other inflammatory diseases driven by aberrant T cell activation.

In collaboration with Drew Adams' Lab, Case Western Reserve University

The brain and blood connection in neurodegeneration

We study how neurodegenerative disorders and hematopoietic function influence each other. Working with Andrew Pieper's lab at CWRU, we are investigating how brain injury alters HSC behavior and how changes in the blood system may in turn affect disease progression in the brain.

This bidirectional relationship between the central nervous system and hematopoiesis is poorly understood. Our work aims to identify molecular signals that cross the brain and bone marrow axis and that could serve as therapeutic targets for both neurological and hematological disease.

In collaboration with Andrew Pieper's Lab, Case Western Reserve University