A programmable arthritis-specific receptor for guided articular cartilage regenerative medicine.
| العنوان: | A programmable arthritis-specific receptor for guided articular cartilage regenerative medicine. |
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| المؤلفون: | Walton BL; Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, 37212, USA., Shattuck-Brandt R; Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, 37212, USA., Hamann CA; Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, 37212, USA., Tung VW; Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, 37212, USA., Colazo JM; Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, 37212, USA., Brand DD; Research Service, Lt. Col. Luke Weathers, Jr. VA Medical Center, Memphis, TN 38105, USA., Hasty KA; Department of Orthopaedic Surgery and Biomedical Engineering, University of Tennessee Health Science Center, Memphis VA Medical Center, Memphis, TN, USA., Duvall CL; Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, 37212, USA.; Center for Bone Biology, Vanderbilt University, Nashville, TN 37212, USA., Brunger JM; 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. |
| المصدر: | BioRxiv : the preprint server for biology [bioRxiv] 2024 Feb 15. Date of Electronic Publication: 2024 Feb 15. |
| نوع المنشور: | Preprint |
| اللغة: | English |
| بيانات الدورية: | Country of Publication: United States NLM ID: 101680187 Publication Model: Electronic Cited Medium: Internet NLM ISO Abbreviation: bioRxiv Subsets: PubMed not MEDLINE |
| مستخلص: | 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 characterized by cartilage degeneration. Methods: An scFv specific for type II collagen (CII) was used to produce a synthetic Notch (synNotch) receptor that enables "CII-synNotch" mesenchymal stromal cells (MSCs) to recognize CII fibers exposed in damaged cartilage. Engineered cell activation by both CII-treated culture surfaces and on primary tissue samples was measured via inducible reporter transgene expression. TGFβ3-expressing cells were assessed for cartilage anabolic gene expression via qRT-PCR. In a co-culture with CII-synNotch MSCs engineered to express IL-1Ra, ATDC5 chondrocytes were stimulated with IL-1α, and inflammatory responses of ATDC5s were profiled via qRT-PCR and an NF-κB reporter assay. Results: CII-synNotch MSCs are highly responsive to CII, displaying activation ranges over 40-fold in response to physiologic CII inputs. 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 TGFβ3 expression resulted in upregulation of Acan and Col2a1 in MSCs, and inducible IL-1Ra expression by engineered CII-synNotch MSCs reduced pro-inflammatory gene expression in chondrocytes. Conclusion: This work demonstrates proof-of-concept that the synNotch platform guides MSCs for spatially regulated, disease-dependent delivery of OA-relevant biologic drugs. |
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| معلومات مُعتمدة: | I01 BX005195 United States BX BLRD VA; P30 CA068485 United States CA NCI NIH HHS; P30 DK058404 United States DK NIDDK NIH HHS; R21 AR079683 United States AR NIAMS NIH HHS |
| تواريخ الأحداث: | Date Created: 20240214 Latest Revision: 20240228 |
| رمز التحديث: | 20240228 |
| مُعرف محوري في PubMed: | PMC10862827 |
| DOI: | 10.1101/2024.01.31.578281 |
| PMID: | 38352576 |
| قاعدة البيانات: | MEDLINE |
| DOI: | 10.1101/2024.01.31.578281 |
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