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Notch-enriched Mesenchymal Stromal Cells for Bone Allograft Repair

Award Number: R01AR073277
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2019
PERIOD OF PERFORMANCE END DATE: 12/31/2025

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Notch-enriched Mesenchymal Stromal Cells for Bone Allograft Repair - Abstract: Segmental long bone defect surgeries require large devitalized allograft transplantations to replace missing host bone segments; however, significant problems often arise due to the impaired ability of the devitalized allograft to incorporate into the host bone. Recently, several discoveries in our lab have provided the basis for selecting, expanding and delivering of a substantial number of mesenchymal stem cells (MSCs), which retain their original stem cell characteristics, to be utilized in skeletal therapeutic applications: i) Notch2-selected and Notch activation by recombinant Jagged1 (JAG1) ligand expanded MSCs possess enhanced potentials for chondrogenic and osteogenic differentiation; ii) MSC sheets generated in temperature-responsive culture dishes exhibit a more robust effect on allograft incorporation into the host bone when transplanted to the site of the defect as a tissue-engineered periosteum surrounding the implanted graft; iii) Notch signaling induces rapid TWIST1 expression in MSCs. Based on these novel findings, we hypothesize that cell sheets generated with JAG1 expanded Notch2 positive MSCs on thermo-responsive culture dishes will significantly enhance critical segmented bone defects healing in a femoral allograft repair mouse model. To test this hypothesis, we will first to determine whether Notch2-selected and JAG1 expanded MSC sheets significantly enhance allograft healing and incorporation using our pre-clinical femoral allograft mouse model, as compared to cell sheets derived from traditionally isolated and expanded MSCs. Second, we will examine whether TWIST1 is require for JAG1-mediated MSC proliferation and maintenance in culture. Finally, we will determine how Notch activation by JAG1 involved in MSC sheet- induced angiogenesis. Data generated by this proposal will likely 1) identify optimized cell populations for generating tissue engineered periosteum (next generation MSC sheets), 2) validate a novel therapeutic approach for enhancing the repair of massive devitalized bone allograft and lead to advances in understanding the mechanism underlying MSC sheet-induced tissue repair, and 3) pave the path for large pre-clinical animal studies and subsequent clinical trials.


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 = $0 )
2025	2024	LOUISIANA STATE UNIVERSITY	1501 KINGS HWY	SHREVEPORT	LA	71103	CADDO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	5	5/1/2025	NON-COMPETING CONTINUATION	$0
2025	2024	LOUISIANA STATE UNIVERSITY	1501 KINGS HWY	SHREVEPORT	LA	71103	CADDO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	1/14/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $305,422 )
2024	2024	LOUISIANA STATE UNIVERSITY	1501 KINGS HWY	SHREVEPORT	LA	71103	CADDO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	5	6/7/2024	NON-COMPETING CONTINUATION	$22,041
2024	2024	LOUISIANA STATE UNIVERSITY	1501 KINGS HWY	SHREVEPORT	LA	71103	CADDO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	11/30/2023	NON-COMPETING CONTINUATION	$283,381
														Subtotal = $305,422

Issue Date FY: 2023 ( Subtotal = $314,868 )
2023	2023	LOUISIANA STATE UNIVERSITY	1501 KINGS HWY	SHREVEPORT	LA	71103	CADDO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	1/14/2023	NON-COMPETING CONTINUATION	$283,381
2023	2023	LOUISIANA STATE UNIVERSITY	1501 KINGS HWY	SHREVEPORT	LA	71103	CADDO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	4	4/20/2023	NON-COMPETING CONTINUATION	$31,487
														Subtotal = $314,868

Issue Date FY: 2022 ( Subtotal = $311,720 )
2022	2022	LOUISIANA STATE UNIVERSITY	1501 KINGS HWY	SHREVEPORT	LA	71103	CADDO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	12/22/2021	NON-COMPETING CONTINUATION	$283,381
2022	2022	LOUISIANA STATE UNIVERSITY	1501 KINGS HWY	SHREVEPORT	LA	71103	CADDO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	3	8/5/2022	NON-COMPETING CONTINUATION	$28,339
														Subtotal = $311,720

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2020	LOUISIANA STATE UNIVERSITY	1501 KINGS HWY	SHREVEPORT	LA	71103	CADDO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	1/29/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $314,868 )
2020	2020	LOUISIANA STATE UNIVERSITY	1501 KINGS HWY	SHREVEPORT	LA	71103	CADDO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	9/24/2020	NON-COMPETING CONTINUATION	$314,868
														Subtotal = $314,868

Issue Date FY: 2019 ( Subtotal = $324,988 )
2019	2019	LOUISIANA STATE UNIVERSITY	1501 KINGS HWY	SHREVEPORT	LA	71103	CADDO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	12/31/2018	NEW	$334,877
2019	2019	LOUISIANA STATE UNIVERSITY	1501 KINGS HWY	SHREVEPORT	LA	71103	CADDO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	1	3/12/2019	NEW	-$9,129
2019	2019	LOUISIANA STATE UNIVERSITY	1501 KINGS HWY	SHREVEPORT	LA	71103	CADDO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	002	1	5/9/2019	NEW	-$760
														Subtotal = $324,988

Grand Total All Awards = $1,571,866

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Notch-enriched Mesenchymal Stromal Cells for Bone Allograft Repair

Award Number: R01AR073277

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/01/2019

PERIOD OF PERFORMANCE END DATE: 12/31/2025

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