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Engineering the Stem Cell Microenvironment for Lymphatic Regeneration

Award Number: R35GM143055
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2021
PERIOD OF PERFORMANCE END DATE: 05/31/2027

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Engineering the Stem Cell Microenvironment for Lymphatic Regeneration - ABSTRACT The lymphatic system is an integral part of the circulatory system, where extracellular fluid flows from vascular capillaries into the lymphatic vessels and is returned to the vascular system via the thoracic duct. Additionally, lymphatic vessels regulate homeostasis of tissue fluid, absorption of dietary fat, and trafficking of immune cells. Consequently, dysfunction in lymphatic vessels is associated with development of many diseases, including obesity and metabolic disease, aging and Alzheimer’s disease, chronic wound and cancer, as well as inflammation and cardiovascular diseases. Therefore, controlling lymphatic vascular formation and augmenting its function is postulated as a promising therapeutic target for preventing and treating these debilitating diseases. Unfortunately, therapeutic lymphangiogenesis has not been widely explored partly due to the unavailability of a clinically-relevant cell source and controllable matrix environment. The overall goal of the research program is to derive lymphatic endothelial cells (LECs) and lymphatic muscle cells (LMCs) from human pluripotent stem cells (hPSCs) that can be used as a clinically-relevant cell source for modeling lymphatic function and physiology, as well as therapeutic lymphangiogenesis in a synthetic and controllable matrix environment. To this end, our lab is at the forefront of developing multi-disciplinary approaches to utilize stem cells and synthetic biomaterials for basic understanding of stem cell differentiation and lymphatic vessel morphogenesis, as well as approaches in therapeutic lymphangiogenesis. We have recently established xeno-free, well-defined and controllable differentiation protocols to direct hPSCs differentiation to clinically-relevant vascular progenitor cells with high reproducibility and efficiency, as well as wide clinical applicability. Furthermore, synthetic matrices can be used to provide spatial and temporal control for these progenitor cells to undergo lymphatic vascular morphogenesis, useful for basic understanding of lymphatic vascular biology and a range of therapeutic applications. These results establish a fundamental link between vascular and lymphatic morphogenesis within synthetic matrices. We are currently focused on bridging the large knowledge gap between molecular understanding of vascular and lymphatic differentiation and morphogenesis in a developmental context. Furthermore, we are also testing the impact of lymphatic vasculature to attenuate inflammatory response, prevent edema, and eventually promote tissue regeneration in a wound healing model. Cumulatively, we are combining approaches in stem cell and bioengineering, biomaterials and microfluidics, as well as lymphatic and systems biology to develop the necessary component in therapeutic lymphangiogenesis: reliable human cell sources from hPSCs within a biologically rational synthetic and controllable matrix environment. Collectively, this research has the potential to not only advance our basic understanding of lymphatic vasculatures in health and disease, but also to revolutionize the way we manage and treat a myriad of diseases that will benefit from innovative therapeutic lymphangiogenesis.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $0 )
2026	2025	UNIVERSITY OF NOTRE DAME DU LAC	940 GRACE HALL	NOTRE DAME	IN	46556	ST JOSEPH	USA	Biomedical Research and Research Training	000	5	4/2/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $391,250 )
2025	2025	UNIVERSITY OF NOTRE DAME DU LAC	940 GRACE HALL	NOTRE DAME	IN	46556	ST JOSEPH	USA	Biomedical Research and Research Training	000	5	5/13/2025	NON-COMPETING CONTINUATION	$391,250
														Subtotal = $391,250

Issue Date FY: 2024 ( Subtotal = $391,250 )
2024	2024	UNIVERSITY OF NOTRE DAME DU LAC	836 GRACE HALL	NOTRE DAME	IN	46556	ST JOSEPH	USA	Biomedical Research and Research Training	000	4	5/28/2024	NON-COMPETING CONTINUATION	$391,250
														Subtotal = $391,250

Issue Date FY: 2023 ( Subtotal = $391,250 )
2023	2023	UNIVERSITY OF NOTRE DAME DU LAC	940 GRACE HALL	NOTRE DAME	IN	46556	ST JOSEPH	USA	Biomedical Research and Research Training	000	3	5/8/2023	NON-COMPETING CONTINUATION	$391,250
														Subtotal = $391,250

Issue Date FY: 2022 ( Subtotal = $640,356 )
2022	2022	UNIVERSITY OF NOTRE DAME DU LAC	940 GRACE HALL	NOTRE DAME	IN	46556	ST JOSEPH	USA	Biomedical Research and Research Training	000	2	6/7/2022	NON-COMPETING CONTINUATION	$391,250
2022	2022	UNIVERSITY OF NOTRE DAME DU LAC	940 GRACE HALL	NOTRE DAME	IN	46556	ST JOSEPH	USA	Biomedical Research and Research Training	001	2	6/10/2022	SUPPLEMENT FOR EXPANSION	$249,106
														Subtotal = $640,356

Issue Date FY: 2021 ( Subtotal = $391,250 )
2021	2021	UNIVERSITY OF NOTRE DAME DU LAC	940 GRACE HALL	NOTRE DAME	IN	46556	ST JOSEPH	USA	Biomedical Research and Research Training	000	1	6/25/2021	NEW	$391,250
														Subtotal = $391,250

Grand Total All Awards = $2,205,356

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Engineering the Stem Cell Microenvironment for Lymphatic Regeneration

Award Number: R35GM143055

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/01/2021

PERIOD OF PERFORMANCE END DATE: 05/31/2027

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