A Mechanotransduction-Aware Strategy for Enhancing MSC Potency via 3D Culture and Localized Delivery

Area of Science:

• Biomaterials Engineering
• Regenerative Medicine
• Cell Therapy

Background:

• Acute lung injury (ALI) involves inflammation, oxidative stress, and fibrosis.
• Mesenchymal stem cell (MSC) therapy for ALI faces challenges with cell retention and microenvironmental integration.
• Existing therapies require improved strategies for sustained therapeutic effects.

Purpose of the Study:

• To engineer a composite hydrogel system (GelMA@hMSCs-Alg-RGD) for enhanced MSC delivery and therapeutic function in ALI.
• To investigate the impact of the engineered microenvironment on MSC behavior and paracrine signaling.
• To evaluate the efficacy of the composite system in preclinical models of ALI.

Main Methods:

• Fabrication of a composite hydrogel using dopamine-modified GelMA and RGD-functionalized alginate microbeads supporting human MSCs.
• In vitro assessment of MSC identity, paracrine factor release, and effects on endothelial and fibroblast cells.
• In vivo evaluation in a murine model of ALI, assessing lung histology, inflammatory markers, oxidative stress, and survival.

Main Results:

• The GelMA@hMSCs-Alg-RGD composite provided a supportive 3D niche, preserving MSC identity and enhancing paracrine potency.
• Engineered MSCs promoted endothelial function and inhibited myofibroblast differentiation.
• In vivo, the composite demonstrated prolonged pulmonary retention, reduced ALI-associated inflammation and oxidative stress, improved survival, and modulated immune cell populations (M1/M2 macrophages).

Conclusions:

• The bioengineered GelMA@hMSCs-Alg-RGD composite system effectively enhances MSC retention and therapeutic outcomes in ALI.
• This strategy integrates localized retention with paracrine signaling to reprogram the lung microenvironment.
• The developed platform offers a broadly applicable approach for MSC-based regenerative medicine.