Faculty Affairs and Academic Programs
M. Kyle Cromer
Life Sciences; Agriculture and Veterinary Sciences
Pooled Screening of Synthetic Receptors to Program Hematopoietic Stem Cell Fate
This project will develop a high-throughput platform to discover synthetic, small-molecule-inducible receptors (“iReceptors”) that modulate hematopoietic stem cell (HSC) fate and enhance production of clinically important blood and immune cells. Building on our inducible EPOR designs, we show this architecture is modular and scalable: more than half of 12 additional receptors tested in primary HSCs demonstrated clear activity, including increased proliferation, STAT5 phosphorylation, and lineage-appropriate transcriptional programs. Aim 1 will generate pooled, barcoded libraries of synthetic receptors incorporating diverse transmembrane and intracellular signaling domains. Using phospho-flow cytometry and barcode sequencing, we will identify receptors that activate specific pathways or confer proliferative advantages in HSCs. Aim 2 will apply these libraries during HSC differentiation into red blood cells, megakaryocytes, and monocytes to discover receptors that enhance lineage specification, maturation, or overall yield. Top candidates will be validated in arrayed assays to refine design and define mechanisms of action. This work is innovative in coupling protein design with high-throughput screening and impactful because it targets major limitations in transfusion and regenerative medicine. Expected outcomes include a generalizable receptor-screening platform and identification of synthetic receptors that enhance production of RBCs, platelets, and monocytes. These tools will accelerate stem-cell-derived therapies and strengthen UCSF’s leadership in next-generation synthetic biology.
