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The effect of donor age on the function and therapeutic efficacy of human hepatocyte-like cells

Award Number: K08AG068374
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 03/15/2021
PERIOD OF PERFORMANCE END DATE: 02/28/2026

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The effect of donor age on the function and therapeutic efficacy of human hepatocyte-like cells - Project Summary: Worldwide, 844 million people are afflicted with liver disease, with mortality nearing 2 million deaths per year. Liver transplantation is the preferred treatment for selected cases but is limited by the availability of high-quality organs from young donors (<55 years old), and the morbidity associated with the operation. Cell-based therapy using primary human hepatocytes (PHHs) is a minimally invasive alternative for treatment of select liver pathologies where architecture is preserved but there are metabolic derangements, such as in acute liver failure and metabolic liver disease. Optimal metabolic function of the cells is critical for the success of cell-based therapies. However, PHH therapy is severely limited by the scarcity of donors, and the dramatic decrease in metabolic function of PHHs from older donors. Human hepatocyte-like cells (h-iHLCs) derived from human induced pluripotent stem cells (h-iPSCs) emerged as an alternative to PHHs for treatment of select liver conditions. H-iHLC have three benefits: (1) H-iHLCs are produced from an unlimited, renewable source: h-iPSCs. (2) They bypass ethical concerns associated with the use of embryonic stem cells. (3) They have the potential to prevent an allogeneic immune response following transplantation by utilizing the patients’ own cells. Although, the deleterious impact of age on the metabolic function has been described for PHHs, the impact of donor age on the metabolism in h-iHLCs has not been studied. Here, we aim to identify the donor age-associated changes in the overall metabolic profile of h-iHLCs by studying the transcriptome and proteome of h-iHLCs from young and old donors and compare the results to PHHs from the same donors. We will study in detail the expression and function of the cytochrome P450 (CYP450) superfamily in h-iHLCs and PHHs as a function of donor age. Age-related changes in DNA-methylation down-regulate metabolic function including CYP450 activity in PHHs. Therefore, we will study and attempt to modulate this regulatory mechanism in h-iHLCs with the goal to optimize the overall metabolic function including CYP450 activity in h-iHLCs. We will examine the therapeutic efficacy of the generated h-iHLCs in a murine model of acute liver failure by transplanting h-iHLCs into metabolic liver failure, tyrosemia type I (Fah¯′¯/Rag2¯′¯/Il2rg¯′¯ on NOD-strain background (FRGN)) mice. The results from this study will provide critical information about the impact of donor age on metabolism and its regulation in h-iHLCs and will (1) assist in selecting metabolically fit donors for allogeneic h-iHLCs transplantation, (2) allow future modulation of functional and regulatory mechanisms through alterations in reprogramming, differentiation and gene editing, to produce high-quality h-iHLCs with optimized metabolic function for allo- and autogeneic transplantation.


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: 2025 ( Subtotal = $165,132 )
2025	2025	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Aging Research	000	5	3/24/2025	NON-COMPETING CONTINUATION	$165,132
														Subtotal = $165,132

Issue Date FY: 2024 ( Subtotal = $165,132 )
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Aging Research	000	4	2/14/2024	NON-COMPETING CONTINUATION	$165,132
														Subtotal = $165,132

Issue Date FY: 2023 ( Subtotal = $165,132 )
2023	2023	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Aging Research	002	3	1/25/2023	NON-COMPETING CONTINUATION	$165,132
2023	2022	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Aging Research	001	2	10/25/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$53,320
2023	2021	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Aging Research	000	1	10/25/2022	NEW	-$53,320
														Subtotal = $165,132

Issue Date FY: 2022 ( Subtotal = $165,132 )
2022	2022	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Aging Research	001	2	7/29/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$165,132
2022	2021	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Aging Research	000	1	7/28/2022	NEW	$0
														Subtotal = $165,132

Issue Date FY: 2021 ( Subtotal = $174,418 )
2021	2021	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Aging Research	000	1	3/12/2021	NEW	$174,418
														Subtotal = $174,418

Grand Total All Awards = $834,946

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The effect of donor age on the function and therapeutic efficacy of human hepatocyte-like cells

Award Number: K08AG068374

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 03/15/2021

PERIOD OF PERFORMANCE END DATE: 02/28/2026

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