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Understanding and regulating skeletal muscle progenitor and stem cell states through metabolic and epigenetic modulation

Award Number: F31AR078640
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

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Project Summary Skeletal muscle is one of the most regenerative tissues in the human body. Skeletal muscle progenitor cells (SMPCs) contribute to developmental myogenesis, and skeletal muscle stem cells (satellite cells, SCs) contribute to postnatal muscle homeostasis and regeneration. In Duchenne Muscular Dystrophy (DMD), a prevalent but fatal X-linked muscle wasting disease that affects 1:5000 live male births, a loss-of-function mutation in the DMD gene results in the absence of functional dystrophin protein to stabilize muscle fibers. This leads to continuous damage from repeated muscle degeneration and regeneration and compromises the regenerative ability of SCs. There is currently no cure for DMD. Differentiating human pluripotent stem cells (hPSCs) into SCs is a valuable resource for developing cell replacement therapies for DMD. However, current hPSC directed myogenic differentiation protocols result in embryonic/fetal-like SMPCs that cannot be maintained over multiple passages (i.e. self-renew) in culture. SMPCs also do not engraft as efficiently as postnatal SCs, and it is not known how to mature SMPCs to SCs because it is unclear how they molecularly differ. Metabolism plays a key role in regulating cell state and function in stem cells across development. We performed single cell RNA sequencing analysis that demonstrated that expression of most genes in glycolysis, tricarboxylic cycle, and oxidative phosphorylation decrease across human myogenic development. However, how metabolic activity supports SMPCs or can be used to transition SMPCs to SCs in humans has not been investigated beyond the transcriptional level. By more closely evaluating the metabolic profiles of tissue-derived SCs and hPSC-derived myogenic subpopulations including hPSC-derived SMPCs (hPSC-SMPCs), specific metabolic enzymes and metabolites in the aforementioned pathways will be targeted as candidates to support hPSC-SMPC self-renewal or promote hPSC-SMPC maturation to SCs in culture. Tightly connected to metabolism is the epigenome which has a direct role in transitioning between cell states, particularly through modulating chromatin accessibility at cis-regulatory regions to mediate transcription factor (TF) binding and control gene expression. Evaluating differences in chromatin accessibility of TF binding motifs between the same myogenic populations identifies TFs that support and regulate SMPC and SC states. Several TF candidates have been identified as potential regulators of SMPC-to-SC maturation. Expression of TF candidates will be modulated to support hPSC-SMPCs or promote their maturation toward SC fate. This work will for the first time shed light on the metabolic and epigenetic roles in maintaining and transitioning between human muscle progenitor and stem cell states. These findings will enhance the regenerative potential of hPSC-derived muscle cells and enable the development of improved myogenic cell therapies for DMD. This study will be performed at the University of California, Los Angeles under the mentorship of Dr. April Pyle, an expert in hPSC and skeletal muscle biology, in my endeavor to becoming a research scientist in the field of regenerative medicine.


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: 2023 ( Subtotal = $43,956 )
2023	2023	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	7/19/2023	NON-COMPETING CONTINUATION	$31,694
2023	2023	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	3	8/7/2023	NON-COMPETING CONTINUATION	$12,262
														Subtotal = $43,956

Issue Date FY: 2022 ( Subtotal = $41,899 )
2022	2022	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	6/28/2022	NON-COMPETING CONTINUATION	$41,899
														Subtotal = $41,899

Issue Date FY: 2021 ( Subtotal = $40,169 )
2021	2021	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	1	5/4/2021	NEW	$0
2021	2021	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	5/4/2021	NEW	$40,169
														Subtotal = $40,169

Grand Total All Awards = $126,024

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Understanding and regulating skeletal muscle progenitor and stem cell states through metabolic and epigenetic modulation

Award Number: F31AR078640

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

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