A programmable arthritis-specific receptor for guided articular cartilage regenerative medicine

Bonnie L Walton; Rebecca Shattuck-Brandt; Catherine A Hamann; Victoria W Tung; Juan M Colazo; David D Brand; Karen A Hasty; Craig L Duvall; Jonathan M Brunger

doi:10.1016/j.joca.2024.12.002

A programmable arthritis-specific receptor for guided articular cartilage regenerative medicine

Osteoarthritis Cartilage. 2024 Dec 18:S1063-4584(24)01501-2. doi: 10.1016/j.joca.2024.12.002. Online ahead of print.

Authors

Bonnie L Walton¹, Rebecca Shattuck-Brandt¹, Catherine A Hamann¹, Victoria W Tung¹, Juan M Colazo¹, David D Brand², Karen A Hasty³, Craig L Duvall⁴, Jonathan M Brunger⁵

Affiliations

¹ Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 37212, USA.
² Research Service, Lt. Col. Luke Weathers, Jr. VA Medical Center, Memphis, TN 38105, USA.
³ Department of Orthopaedic Surgery and Biomedical Engineering, University of Tennessee Health Science Center, Memphis VA Medical Center, Memphis, TN 38105, USA.
⁴ Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 37212, USA; Center for Bone Biology, Vanderbilt University, Nashville, TN 37212, USA.
⁵ Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 37212, USA; Center for Bone Biology, Vanderbilt University, Nashville, TN 37212, USA; Center for Stem Cell Biology, Vanderbilt University, Nashville, TN 37212, USA. Electronic address: jonathan.m.brunger@vanderbilt.edu.

PMID: 39706287
DOI: 10.1016/j.joca.2024.12.002

Abstract

Objective: Investigational cell therapies have been developed as disease-modifying agents for the treatment of osteoarthritis (OA), including those that inducibly respond to inflammatory factors driving OA progression. However, dysregulated inflammatory cascades do not specifically signify the presence of OA. Here, we deploy a synthetic receptor platform that regulates cell behaviors in an arthritis-specific fashion to confine transgene expression to sites of cartilage degeneration.

Design: A single-chain variable fragment specific for type II collagen (CII) that is exposed in damaged cartilage was used to produce a synthetic Notch (synNotch) receptor that enables "CII-synNotch" mesenchymal stromal cells (MSCs) to recognize degraded cartilage. Artificial signaling induced by both CII-treated culture surfaces and primary tissues was measured via fluorescence and luminescence assays. Separate studies measured the ability of CII-synNotch to govern cartilage anabolic activity of MSCs. Finally, a co-culture with ATDC5 chondrocytes was used to determine whether CII-synNotch MSCs can protect chondrocytes against deleterious effects of pro-inflammatory interleukin-1 in a CII-dependent manner.

Results: CII-synNotch MSCs are highly and selectively responsive to CII, but not type I collagen, as measured by luminescence assays, fluorescence microscopy, and concentrations of secreted transgene products in culture media. CII-synNotch cells exhibit the capacity to distinguish between healthy and damaged cartilage tissue and constrain transgene expression to regions of exposed CII fibers. Receptor-regulated production of cartilage anabolic and anti-inflammatory transgenes was effective to mediate cartilage regenerative functions.

Conclusion: This work demonstrates proof-of-concept that the synNotch platform guides MSCs for spatially regulated, disease-dependent delivery of OA-relevant biologic drugs.

Keywords: Cell therapy; Osteoarthritis; SynNotch; Synthetic biology.