Dissecting Spatial and Molecular Dynamics of Immune-Vascular Crosstalk to Overcome ImmuneBarriers in iPSC-Based Therapies

About This Grant

PROJECT SUMMARY/ABSTRACT Induced pluripotent stem cells (iPSCs) offer a promising platform for regenerative medicine, with their ability to self-renew indefinitely and differentiate into vascular cells. However, their clinical translation in vascular diseases is limited by major challenges: the impracticality of autologous therapy, immune rejection in allogeneic transplantation, and inefficient differentiation. Allogeneic iPSC-derived cells are rapidly recognized and eliminated by the host immune system, triggering both innate and adaptive immune responses. Additionally, current differentiation protocols yield vascular cells with low and inconsistent efficiency (~20%), limiting scalability and therapeutic viability. To overcome these challenges, this study aims to engineer hypoimmunogenic iPSC-derived vascular cells that evade immune detection while efficiently integrating into host vasculature. Simultaneously, spatial transcriptomics will be utilized to map immune- vascular interactions and uncover pathways that drive immune tolerance and vascular remodeling. To overcome differentiation inefficiencies, we have developed a transcription factor-driven strategy using ETV2 and NKX3.1, enabling >95% efficiency in generating endothelial and mural progenitor cells, respectively. Their ability to integrate and enhance perfusion will be tested in ischemic hindlimb models. The project comprises three aims. First, we will engineer hypoimmunogenic vascular cells by knocking out B2M/CIITA to eliminate highly polymorphic MHC expression, preventing adaptive immune recognition and overexpressing CD47 to prevent innate immune clearance. Second, we will assess vascular integration and perfusion enhancement in ischemic models by transplanting the engineered vascular cells. Third, we will apply multiplexed spatial transcriptomics to map immune-vascular interactions, identifying pathways that regulate immune evasion and vascular remodeling. This study will provide critical insights into immune-vascular dynamics, establishing a foundation for hypoimmunogenic iPSC-based therapies that achieve long-term immune tolerance and functional vascular regeneration in ischemic diseases. The training will occur under the mentorship of Dr. Juan Melero-Martin at Boston Children's Hospital/Harvard Medical School. I will be co-mentored by an extraordinary team of scientists on my advisory committee, including Dr. Torsten Meissner and Dr. Kaifu Chen, for new training goals in immune biology, vascular biology, transcriptomics as well as career guidance. Through this training, I will acquire advanced conceptual, technical, and professional skills, preparing me for an independent research career in translational regenerative medicine.