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Optimization of the engineered 3D hepatic microenvironment enhances pluripotent stem cell derived hepatocyte

Award Number: R01DK121072
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary/Abstract Liver disease is a growing clinical problem in the United States and worldwide affecting 30 million Americans resulting in 750,000 hospitalizations and 36,000 deaths yearly. Unfortunately, unlike other common diseases such as cardiovascular diseases, the incidence of liver disease and its associated complications are increasing. Given the steady rise of patients with liver disease, the demand for liver transplantation has continued to increase while the supply of organs has remained unchanged creating a pressing need to address this organ scarcity. Proposed alternatives to organ transplantation are the transplantation of cells but human hepatocytes are similarly difficult to source. As a result, there are currently no alternatives for obtaining robust functional hepatocytes which is significantly hampering scientific study and the development of more effective clinical therapies; our work addresses this significant research and clinical gap. Pluripotent stem cell derived hepatocyte-like cells are often cited as a potential alternative cell source for organ transplants and as a platform for pharmaceutical and scientific study. However, the current inability to derive robust and fully mature hepatocytes limits the clinical and scientific utility of currently produced cells. Pluripotent stem cell fate and hepatocyte maturation is determined by the complex array of internal signals and external cues from the microenvironment. Unfortunately our current differentiation platforms do not mimic the cellular, extracellular matrix (ECM), and 3D complexities of the in vivo hepatic microenvironment and therefore the role of ECM-cell and cell-cell interactions in the differentiation process remains largely unknown. Our central hypothesis is that the 3D microenvironment and subsequent cellular interactions (e.g. cell-ECM and cell-cell interactions) dictates cell fate decisions and it is through these factors by which fetal cell types mature into terminally differentiated cell types. In recent work our group has developed robust tools to systematically and efficiently manipulate the 3D microenvironment. The central goal of this proposal is to identify and examine important inductive cellular interactions for directed pluripotent stem cell differentiation in vitro to enable the generation of phenotypically and functionally mature hepatocytes. We will systematically examine and identify the role cell-cell and cell- ECM interactions play in regulating the fetal to adult hepatocyte transition and will incorporate these findings into our current differentiation and tissue engineered constructs. These optimized 3D multicellular spheroids platforms will enable scientific study and the development of more effective clinical therapies.


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: 2024 ( Subtotal = $343,238 )
2024	2024	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	1/12/2024	NON-COMPETING CONTINUATION	$343,238
														Subtotal = $343,238

Issue Date FY: 2023 ( Subtotal = $381,375 )
2023	2023	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	1/20/2023	NON-COMPETING CONTINUATION	$381,375
														Subtotal = $381,375

Issue Date FY: 2022 ( Subtotal = $381,375 )
2022	2022	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	3/30/2022	NON-COMPETING CONTINUATION	$38,138
2022	2022	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	2/25/2022	NON-COMPETING CONTINUATION	$343,237
														Subtotal = $381,375

Issue Date FY: 2021 ( Subtotal = $758,146 )
2021	2021	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	2/13/2021	NON-COMPETING CONTINUATION	$758,146
														Subtotal = $758,146

Issue Date FY: 2020 ( Subtotal = $762,750 )
2020	2020	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	407 E 61ST ST RM 106 1ST FL	NEW YORK	NY	10065	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	1/27/2020	NEW	$381,375
2020	2020	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	407 E 61ST ST RM 106 1ST FL	NEW YORK	NY	10065	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	1	9/10/2020	SUPPLEMENT FOR EXPANSION	$381,375
														Subtotal = $762,750

Grand Total All Awards = $2,626,884

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Optimization of the engineered 3D hepatic microenvironment enhances pluripotent stem cell derived hepatocyte

Award Number: R01DK121072

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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