CERSI Collaborators: University of Stanford: Ngan Huang, PhD

FDA Collaborators: Center for Biologics Evaluation and Research: Kyung Sung, PhD; Johnny Lam, PhD

Project Start Date: July 2019

Regulatory Science Challenge

Multipotent stromal cells (MSCs) reside in many tissues, including the bone marrow and fat. MSCs are important because they can turn into a wide range of specialized cells, secrete therapeutic factors, and influence immune responses. Human MSCs are a promising therapeutic cell type that is currently being tested in clinical trials for treatment of cardiovascular disease, neurological diseases, and cancer. However, a limiting step in the application of MSCs for clinical testing is the establishment of robust methodologies to manufacture and characterize these cells to optimize the quality and consistency of cells obtained from multiple donors.

Project Description and Goals

Tissue chips are in vitro devices that model the physiological environments of bone marrow and fat tissue where MSCs reside in humans. The extracellular matrix (ECM) of these tissues consists of a complex mix of biomolecules that influence the cellular characteristics and biological composition of the MSCs. These microenvironmental factors are different from conventional Petri dishes, which are much stiffer than physiological conditions and lack the complex ECMs found in the native environment.

Accordingly, the goal of this project is to develop a tissue chip for high-throughput systematic control of ECM chemical composition and stiffness to identify microenvironmental conditions that optimize cell culture and differentiation. If the proposed objectives are successful, this tissue chip could become a platform to identify qualified cells for clinical application, which could lead to an improvement in the quality and safety of FDA-regulated regenerative medicine cellular products for patient use.

Research Outcomes/Results

Findings based on analyzing MSC expansion and differentiation suggest that the cells respond often times much better in the presence of in complex ECM cue, compared to simplified single-factor ECM cues. In addition, the stiffness of the ECM environment also plays a strong role in promoting cell growth and differentiation, as confirmed by analysis of gene and protein expression.

Research Impacts

Findings suggest that complex ECM environments may be better suited for manufacturing MSCs, compared to conventional Petri Dishes. These findings can impact the way that MSCs are manufactured prior to therapeutic cell delivery for clinical testing.

Publications

Chan AH, Huang NF. Effects of nicotine on the translation of stem cell therapy. Regen Med. 2020 May;15(5):1679-1688. doi: https://doi.org/10.2217/rme-2020-0032. Epub 2020 Jul 3. PMID: 32618492; PMCID: PMC7466930.

Chan AHP, Huang NF. Engineering Cardiovascular Tissue Chips for Disease Modeling and Drug Screening Applications. Front Bioeng Biotechnol. 2021 Apr 20;9:673212. doi: https://doi.org/10.3389/fbioe.2021.673212. PMID: 33959600; PMCID: PMC8093512.