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  1. Advancing Regulatory Science

The Regulatory Effect of Substrate Mechanical Properties on the Production and Immunomodulation Efficacy of Mesenchymal Stem Stromal Cells

CERSI Collaborators: Dr. Luo Gu, Johns Hopkins University Whiting School of Engineering

FDA Collaborators: Dr. Kyung Sung, Principal investigator at the Office of Therapeutic Products (OTP), CBER

Project Start Date: July 9, 2021
Project End Date: October 31, 2023

Regulatory Science Challenge

Stem/stromal cell transplantation is an emerging strategy for regenerative medicine and treating inflammatory and autoimmune diseases. For example, mesenchymal stem/stromal cell (MSC) therapy has shown promising safety and efficacy results in recent clinical trials. However, the regulatory knowledge about this emerging therapeutic is lacking. MSC products tend to have poor lot-to-lot consistency and it has been difficult to assess MSC quality attributes. This is in part due to the complex manufacturing process of cell-based products.

Project Description and Goals

Mesenchymal stem/stromal cells (MSCs) are being widely studied for regenerative medicine and immune regulation applications. For example, MSC transplantation represents a promising therapeutic intervention for inflammatory diseases, and there are currently over 400 clinical trials investigating the immunomodulation function of MSCs for the treatment of Graft versus host disease (GVHD), chronic heart failure, Crohn’s disease, etc. However, MSCs are heterogeneous and have multi-modal activity, which is a major challenge for MSC product development and quality control. The overarching goal of the project is to better understand and improve MSC manufacturing. Different from conventional therapeutics, cell products need to be manufactured using cell culture. Cell culture conditions such as the physical properties of culture substrates are known to direct cell activity and functions. The project examines how the mechanical properties of culture substrates regulate human MSCs’ production and immunomodulation efficacy. This study will both improve understanding of fundamental MSC biology and advance regulatory science in cell manufacturing and quality control.

Research Outcomes/ Results

In this FDA-JHU CERSI project, investigators developed new hydrogels with tunable stiffness and viscoelasticity as important tools to study the effect of substrate mechanical properties on MSC’s production and immunosuppressive capacity. This study revealed that substrate mechanical properties regulates the proliferation, immunosuppression-related gene expression, and immunosuppressive capacity of human MSCs. In addition, the effects of substrate stiffness and viscoelasticity persisted after hMSCs were extract from hydrogels, which indicates hMSCs can maintain mechanical memory of past culture conditions. These findings have identified that stiffness and viscoelasticity are important factors regulating MSC’s production and immunosuppressive capacity, and their effect during the manufacturing of MSCs will likely persist for subsequent in vivo applications.

Overall, this study has provided new knowledge on how the mechanical properties of culture substrate regulate MSCs’ characteristics, production, and immunomodulation efficacy, which are important issues for manufacturing MSC-based products. This study algins with FDA’s priority area in supporting new approaches to improve product manufacturing and quality in FDA’s Strategic Plan for Regulatory Science.

Research Impacts

This study has identified that substrate mechanical properties are important factors regulating MSC’s production and immunosuppressive capacity, and their effect during the manufacturing of MSCs will likely persist for subsequent in vivo applications. The findings will likely advance the regulatory knowledge on MSC-based therapies.

Publication to date:
Brian J Kwee, Johnny Lam, Adovi Akue, Mark A KuKuruga, Kunyu Zhang, Luo Gu, Kyung E Sung. “Functional heterogeneity of IFN-γ-licensed mesenchymal stromal cell immunosuppressive capacity on biomaterials”, Proceedings of the National Academy of Sciences, 118 (35), 2021.
PMID: 34446555

 

 

 
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