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Dissect the mechanisms underlying interspecies pluripotent stem cell competition

Award Number: R01HD103627
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/18/2022
PERIOD OF PERFORMANCE END DATE: 12/31/2026

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Dissect the mechanisms underlying interspecies pluripotent stem cell competition - PROJECT SUMMARY/ABSTRACT Shortage of organs for transplantation is one of the largest unmet medical needs. Researchers are currently working on a variety of ways to increase the number of organs available. Recently, the prospect of producing human organs in animals via interspecies blastocyst complementation has raised important attention and may constitute an innovative approach to overcome the worldwide shortage of donor organs. Interspecies blastocyst complementation works by injecting donor pluripotent stem cells (PSCs) from one species into the organogenesis-disabled blastocyst of a different species. The growing host embryo can provide an emptied developmental organ niche for donor cells to occupy. Despite the potential, however, recent work revealed that although donor PSCs can initially engraft to inner cell mass (ICM) of blastocysts from distantly related host species, their chimeric contribution to early post-implantation stages is low. These results suggest the existence of embryonic xenogeneic barriers between evolutionarily distant species. Unlike chimera formation within the same species, a multitude of factors can differ significantly between species, which preclude robust chimerism. Cell competition, a conserved fitness-sensing process during which fitter cells eliminate neighboring less-fit but viable cells, has been proposed as a surveillance mechanism to ensure normal development and tissue homeostasis, and has also been suggested to act as a barrier to interspecies chimerism. During chimera formation, xenogeneic donor PSCs may be treated as unfit or aberrant cells and targeted for elimination. Most recently, we developed an interspecies PSC co-culture strategy and discovered a previously unknown mode of cell competition between species. Interspecies competition between PSCs occurred in primed but not naive pluripotent cells, and between evolutionarily distant species. By comparative transcriptome analysis, we found that genes related to the NF-κB and p53 signaling pathways, among others, were upregulated in less-fit ‘loser’ human cells. Genetic inactivation of TP53, a core component (P65, also known as RELA) and an upstream regulator (MYD88) of the NF-κB complex in human PSCs could overcome their competitive elimination by co- cultured mouse PSCs, thereby improving the survival and chimerism of human cells in early mouse embryos. Based on extensive preliminary results, in this proposal, we will further dissect the mechanisms underlying interspecies primed PSC competition in both loser and winner cells. And, by suppressing interspecies PSC competition, we aim to improve chimerism and provide the proof-of-concept of interspecies blastocyst complementation from donor PSCs of rhesus monkey, our close kin, in distantly related mouse host.


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 = $317,340 )
2026	2026	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Child Health and Human Development Extramural Research	000	5	12/12/2025	NON-COMPETING CONTINUATION	$317,340
														Subtotal = $317,340

Issue Date FY: 2025 ( Subtotal = $352,600 )
2025	2025	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Child Health and Human Development Extramural Research	001	4	4/11/2025	NON-COMPETING CONTINUATION	$35,260
2025	2025	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Child Health and Human Development Extramural Research	000	4	12/16/2024	NON-COMPETING CONTINUATION	$317,340
														Subtotal = $352,600

Issue Date FY: 2024 ( Subtotal = $349,074 )
2024	2024	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Child Health and Human Development Extramural Research	001	3	5/1/2024	NON-COMPETING CONTINUATION	$31,734
2024	2024	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Child Health and Human Development Extramural Research	000	3	12/19/2023	NON-COMPETING CONTINUATION	$317,340
														Subtotal = $349,074

Issue Date FY: 2023 ( Subtotal = $352,600 )
2023	2023	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Child Health and Human Development Extramural Research	000	2	12/16/2022	NON-COMPETING CONTINUATION	$317,340
2023	2023	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Child Health and Human Development Extramural Research	001	2	2/10/2023	NON-COMPETING CONTINUATION	$35,260
														Subtotal = $352,600

Issue Date FY: 2022 ( Subtotal = $352,600 )
2022	2022	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Child Health and Human Development Extramural Research	000	1	2/17/2022	NEW	$352,600
														Subtotal = $352,600

Grand Total All Awards = $1,724,214

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Dissect the mechanisms underlying interspecies pluripotent stem cell competition

Award Number: R01HD103627

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/18/2022

PERIOD OF PERFORMANCE END DATE: 12/31/2026

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