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A renewable and genetically tractable human stem cell-derived multicellular platform for the study of fibrotic liver diseases

Award Number: R01DK125100
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 Fibrotic liver disease is a growing public health concern significantly impacting the global population. Fibrotic liver disease is often the result of sustained insults; chronic viral hepatitis B and C as well as NAFLD are the most prevalent causes. While antiviral regimens for hepatitis B and C have decreased the viral cirrhosis burden, other causes like NAFLD are increasingly prevalent, now affecting 14-27% of individuals in developed countries. Despite this high disease burden, there are currently no approved therapies. Rather, the lack of consensus on optimal drug targets or strategies reflects a gap in our mechanistic understanding of disease drivers. Similarly, the utility and clinical relevance of animal models is equally controversial. A multitude of models are currently used, but each recapitulates only isolated aspects of human pathophysiology. There is an unmet need for human-relevant systems that recapitulate key elements of fibrotic liver disease to enable mechanistic dissection. The measurable improvement in liver fibrosis in some but not all patients following successful antiviral treatment reinforces the need for better understanding of fibrogenesis at a molecular level to aid development of new treatments to prevent fibrosis or encourage regression. For NAFLD, despite identification of increasing numbers of susceptibility-associated genetic variants and lifestyle-dependent risk factors, the mechanisms by which they individually or synergistically contribute to disease progression remain largely unclear. The primary research goal of this proposal is to exploit a unique renewable and genetically manipulatable human pluripotent stem cell (hPSC)-derived multicellular culture system to address the aforementioned gaps. In this multicellular system, we coculture hPSC-derived hepatocytes, hepatic stellate cells (HSCs), and macrophages in a manner that recapitulates the complexity of liver physiology in both health and disease. Modeling hepatitis virus infection and NAFLD in the multicellular cultures, we found that both HCV infection and a lipotoxic milieu induced inflammatory signals and stellate cell activation. A lipotoxic milieu also triggered other features of NAFLD clinical phenotypes. Eliminating HCV reversed fibrosis-like phenotypes and treating with obeticholic acid showed improvement in NAFLD-like features, as observed in the clinic. Across three aims, using cell and molecular approaches, we capitalize on the unique features of this novel platform to address questions that cannot be adequately answered with any existing ex vivo human-relevant system, including the roles of cytokines in HSC activation (Aim 1), the mechanisms of reversion after activation (Aim 2) and the role of genetics and lifestyle-associated risk factors in NAFLD (Aim 3). Understanding the molecular mechanisms of stellate cell activation and fibrosis development are critical for developing diagnostics and designing new treatments to block fibrosis or promote regression. In addition, elucidating the mechanisms of how genetic variants and risk factors contribute to liver disease progression may offer the opportunity to craft targeted antifibrotic interventions optimized for particular patient subgroups.


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 = $446,226 )
2024	2024	ROCKEFELLER UNIVERSITY	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	2/23/2024	NON-COMPETING CONTINUATION	$446,226
														Subtotal = $446,226

Issue Date FY: 2023 ( Subtotal = $494,315 )
2023	2023	ROCKEFELLER UNIVERSITY	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	2/22/2023	NON-COMPETING CONTINUATION	$494,315
														Subtotal = $494,315

Issue Date FY: 2022 ( Subtotal = $494,315 )
2022	2022	ROCKEFELLER UNIVERSITY, THE	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	4/4/2022	NON-COMPETING CONTINUATION	$49,433
2022	2022	ROCKEFELLER UNIVERSITY, THE	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	2/18/2022	NON-COMPETING CONTINUATION	$444,882
														Subtotal = $494,315

Issue Date FY: 2021 ( Subtotal = $509,922 )
2021	2021	ROCKEFELLER UNIVERSITY, THE	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	2/26/2021	NEW	$509,922
														Subtotal = $509,922

Grand Total All Awards = $1,944,778

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A renewable and genetically tractable human stem cell-derived multicellular platform for the study of fibrotic liver diseases

Award Number: R01DK125100

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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