Hematopoietic stem and progenitor cell (HSPC) transplantation is a lifesaving therapy for otherwise incurable hematopoietic malignancies or bone marrow failure. Graft success after intravenous infusion requires donor HSPC migration to specialized, highly vascularized marrow niches, where progenitor cells can reconstitute a clonally diverse blood and immune system. Clinically achieving optimal transplantation requires a minimum dose of HSPCs; however, this can be constrained by patient age and disease status, particularly in autologous transplants.
The laboratory of Dr. Stephanie Hurwitz, MD, PhD seeks to better understand the interaction of HSPCs with the bone marrow microenvironment. One mechanism of HSPC crosstalk with supportive niche cells is via the secretion and uptake of nanoscale extracellular vesicles (EVs) that carry bioactive cargo including proteins, lipids, and nucleic acids. Using a variety of in vitro and in vivo models, the Hurwitz lab studies the complex HSPC-niche signaling, including through EVs, that underlies physiologic and therapeutic mechanisms of HSPC marrow homing and niche occupancy. The long-term goal of the lab is to develop novel, non-toxic strategies to improve patient outcomes after HSPC transplantation.
Active Research
Investigating the interplay between the HSPC vesicle secretome and long-term cellular function
We have previously described a link between sphingomyelinase-dependent EV secretion and the integrated stress response (ISR) as a key modulator of HSPC homeostasis and long-term fitness. Using cutting-edge RNA and genome sequencing techniques combined with functional studies, we aim to understand how HSPC vesicles fine-tune cellular function, particularly under regenerative stress such as transplantation.
Defining the role of HSPC vesicles in modulating engraftment through endothelial cell crosstalk
During transplantation, HSPC migration from the circulation to the bone marrow relies upon interaction with sinusoidal endothelial cells. Canonical homing to the bone marrow occurs along the CXCR4-CXCL12 axis. In addition, we recently uncovered a novel CCR2-dependent signaling pathway that promotes enhanced HSPC homing via EV crosstalk with endothelial cells. The Hurwitz lab is investigating key EV cargo that drive endothelial cell remodeling and guide transplantation niche establishment.
Leveraging HSPC-EC crosstalk to optimize transplantation outcomes
Understanding mechanisms of physiologic HSPC-niche communication during bone marrow engraftment is crucial to lay a foundation for exploring novel strategies to enhance therapeutic transplantation. However, delivery of molecular cargo by biologic EVs currently harbors numerous limitations. Through ongoing collaborations, the Hurwitz lab is interested in exploiting physiologic HSPC-niche interactions through synthetic cargo delivery to enhance HSPC engraftment after transplantation.
Highlighted Publications
A full list of publications by Stephanie Hurwitz, MD, PhD, are available on PubMed.
Hurwitz SN, Kobulsky DR, Jung SK, Chia JJ, Butler JM, Kurre P. CCR2 cooperativity promotes hematopoietic stem cell homing to the bone marrow. Science Advances. 2024. In press.
Chen DW, Fan JM, Schrey JM, Mitchell DV, Jung SK, Hurwitz SN, Perez EB, Muraro MJ, Carroll M, Taylor DM, Kurre P. Inflammatory recruitment of healthy hematopoietic stem and progenitor cells in the acute myeloid leukemia niche. Leukemia. 2024 Apr;38(4):741-750. PMID: 38228679.
Hurwitz SN, Jung SK, Kobulsky DR, Fazelinia H, Spruce LA, Pérez EB, Groen N, Mesaros C, Kurre P. Neutral sphingomyelinase blockade enhances hematopoietic stem cell fitness through an integrated stress response. Blood. 2023 Nov 16;142(20):1708-1723. PMID: 37699202.
Hurwitz SN, Jung SK, Kurre P. Hematopoietic stem and progenitor cell signaling in the niche. Leukemia. 2020 Dec;34(12):3136-3148. PMID: 33077865.
