Grants We Funded

Abstract

Impact Statement: Stem cell promotes regeneration via a cocktail of growth factors, cytokines, chemokines, and exosomes, called the secretome. The secretome from an induced pluripotent stem cell (iPSC)-derivatives may be a novel and promising source of cell-based yet cell-free therapy for wound healing. The objectives of this project are to harness this secretome, determine the composition, and develop methods to achieve optimal therapeutic efficacy. The ultimate goal is to manufacture an off-the-shelf ready-to-go cell-free product from iPSC with fewer safety concerns while maintaining its benefits. It will situate the iPSC-derived cell-free therapy at the forefront of next-generation regenerative wound healing applications.

Project Summary: The long-term goal of this research proposal is to manufacture an off-the-shelf product generated from pluripotent stem cells (PSC) for wound healing application. While stem cell has gained interest as a promising approach for the treatment of wounds, there is limited success in the clinic. Poor stem cell implantation is still a challenge. Recent reports indicate that secretome, a cocktail of paracrine factors and exosomes, controls stem cell function. The idea of using secretome instead of stem cells is thus a paradigm shift from traditional stem cell therapy. The future of cell therapy is thus in understanding the secretory function of these stem cells and developing bioengineered tools that can help deliver secretome for optimal therapeutic efficacy. In this study, we propose to exploit the secretome of PSC-derived vascular smooth muscle cells (VSMC) as a novel strategy for wound healing. We have already generated integration-free human iPSCs and differentiated them to pure and functional iVSMCs in abundance. While studies, including ours, have shown the potentials of iVSMC in promoting wound healing, their full regenerative potential is yet to be determined. In Aim 1, we will focus on isolating and characterizing exosomes from iVSMC (iVSMC-Exo). We postulate that the iVSMC-Exo will act similarly to iVSMC and will promote wound healing. Our preliminary data demonstrate the presence of various growth factors, cytokines, and exosomes in the conditioned medium (iVSMC-CM). Additionally, the iVSMC-CM shows wound healing potential by promoting proliferation, migration, and angiogenesis, and immunomodulation. In Aim 2, we will design a biomaterial for extended retention and sustained delivery of the secretome. We hypothesize that this novel strategy will enhance the therapeutic efficacy of the secretome. We have already established protocols to fabricate an injectable hydrogel using natural polymers and a non-toxic cross-linker. The successful completion of the proposal will help in determining the wound healing potential of iVSMC-Exo and optimizing the delivery methods to achieve optimal therapeutic efficacy.

Biography
I am an Associate Research Scientist in the department of surgery (plastic) at Yale University in Dr. Henry Hsia’s laboratory. I have spent the last 14 years working in several laboratories across India, Ireland, and the US exploring different aspects of biomaterial design and stem cell. I did my postdoctoral work with Drs. Henry Hsia, a surgeon-scientist, and Yibing Qyang, a stem cell scientist, on induced pluripotent stem cells, vascular tissue engineering, and wound healing. My doctoral research with Dr. Abhay Pandit, a biomaterial expert, was on developing functionalized biomaterials for the delivery of therapeutic genes to treat limb ischemia. I have worked with various biomaterial platforms including injectable hydrogels for the delivery of genes and stem cells. I also have extensive expertise in the culture and differentiation induced pluripotent stem cell (iPSC). During my postdoctoral, I have established a reproducible protocol to generate millions of vascular smooth muscle cells (iVSMCs) from iPSC. I have already used these cells to develop various tissue engineering platforms. My preliminary data demonstrate an abundant amount of growth factor, cytokines, and exosome secretion from iVSMCs. In this current proposal, I will isolate and characterize exosomes for their wound healing potentials. Furthermore, I will harness the secretome from iVSMC and use it as a cell-free therapeutic in combination with an injectable hydrogel.