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Mechanical programming to enhance the immunosuppressive function of mesenchymal stem cells for the treatment of graft-versus-host disease

Award Number: R01HL179424
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2026
PERIOD OF PERFORMANCE END DATE: 06/30/2030

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Mechanical programming to enhance the immunosuppressive function of mesenchymal stem cells for the treatment of graft-versus-host disease - PROJECT SUMMARY Mesenchymal stem/stromal cells (MSCs) are potent regulators of immune cells, and their immunosuppressive function is being actively investigated for a number of therapeutic applications. In particular, it has been demonstrated that MSCs can inhibit the proliferation of effector T cells and induce regulatory T-cell differentiation for treating graft versus host disease (GvHD). A few MSC products have been approved by regulatory agencies in countries outside of the U.S. However, MSCs have not always shown consistent efficacy in GvHD clinical trials. This is in part due to the challenges of generating MSCs with high therapeutic potency. The overarching goal of this project is to develop MSC therapies with enhanced immunosuppressive efficacy for GvHD treatment by identifying and providing optimal microenvironment mechanical cues in MSC production. Mechanical cues from cell microenvironment play important roles in regulating cell behavior. For example, studies have shown that matrix stiffness directs cell activity and fate such as migration, proliferation, and differentiation. However, matrix or material stiffness only describes their static, elastic mechanical property. Instead of being simply elastic, natural extracellular matrix (ECM) and living tissues are viscoelastic, exhibiting stress relaxation over different characteristic time scales (stress relaxes at different rates). We have developed a hydrogel system that can recapitulate the stiffness and viscoelastic behavior of different types of tissues. Using the hydrogels as culture substrates, we discovered that matrix stress relaxation, in addition to stiffness, is an important mechanical factor regulating cell–ECM interactions and directing MSC activities including spreading, proliferation, differentiation, and in vivo bone regeneration. In collaboration with Dr. Kyung Sung at FDA, we recently found that substrate stress relaxation also regulates MSC's immunosuppressive capacity and their ability to inhibit T cell proliferation; Interestingly, MSCs retained their mechanical “memory” even after being extracted from the hydrogels (preliminary data). In light of these new findings, we hypothesize that biomaterials with tailored stress relaxation properties can provide inducing mechanical cues in MSC production to enhance MSC's immunosuppressive efficacy for GvHD treatment. We will test this hypothesis in the following specific aims: Aim 1: Elucidate the molecular mechanisms by which matrix stress relaxation regulates the immunosuppressive capacity of human MSCs (hMSC) derived from bone marrow. Aim 2: Compare the effect of matrix stress relaxation on hMSCs derived from different donors and tissues, and examine the influence of stiffness in the fast stress relaxing environment. Aim 3: Evaluate the efficacy of hMSCs primed by viscoelastic hydrogels with different stress relaxation properties for GvHD treatment in an animal model. Successful completion of these aims will have significant impact in understanding how matrix mechanical cues regulates the immunosuppressive capacity of hMSCs, with the findings potentially leading to better treatment for GvHD.


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 = $379,509 )
2026	2026	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Blood Diseases and Resources Research	000	1	6/26/2026	NEW	$379,509
														Subtotal = $379,509

Grand Total All Awards = $379,509

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Mechanical programming to enhance the immunosuppressive function of mesenchymal stem cells for the treatment of graft-versus-host disease

Award Number: R01HL179424

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2026

PERIOD OF PERFORMANCE END DATE: 06/30/2030

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