Low-dose xenogeneic mesenchymal stem cells target canine osteoarthritis through systemic immunomodulation and homing

Charlotte Beerts; Sarah Y Broeckx; Eva Depuydt; Liesa Tack; Lore Van Hecke; Koen Chiers; Leen Van Brantegem; Gabriele Braun; Klaus Hellmann; Nathalie de Bouvre; Nathalie Van Bruaene; Tine De Ryck; Luc Duchateau; Bernadette Van Ryssen; Kathelijne Peremans; Jimmy H Saunders; Geert Verhoeven; Glenn Pauwelyn; Jan H Spaas

doi:10.1186/s13075-023-03168-7

Low-dose xenogeneic mesenchymal stem cells target canine osteoarthritis through systemic immunomodulation and homing

Arthritis Res Ther. 2023 Oct 3;25(1):190. doi: 10.1186/s13075-023-03168-7.

Authors

Charlotte Beerts^{1

2}, Sarah Y Broeckx¹, Eva Depuydt^{1

3}, Liesa Tack¹, Lore Van Hecke¹, Koen Chiers⁴, Leen Van Brantegem⁴, Gabriele Braun⁵, Klaus Hellmann⁵, Nathalie de Bouvre⁶, Nathalie Van Bruaene⁷, Tine De Ryck⁷, Luc Duchateau⁸, Bernadette Van Ryssen², Kathelijne Peremans², Jimmy H Saunders², Geert Verhoeven², Glenn Pauwelyn⁹, Jan H Spaas^{2

10}

Affiliations

¹ Boehringer Ingelheim Veterinary Medicine Belgium, Noorwegenstraat 4, 9940, Evergem, Belgium.
² Department of Morphology, Imaging, Orthopedics, Rehabilitation and Nutrition of Domestic Animals, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, 9820, Merelbeke, Belgium.
³ Department of Surgery and Anesthesiology of Domestic Animals, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, 9820, Merelbeke, Belgium.
⁴ Department of Pathology, Bacteriology and Poultry diseases, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, 9820, Merelbeke, Belgium.
⁵ Klifovet AG, Geyerspergerstrasse 27, 80689, Munich, Germany.
⁶ Private Referral Veterinary Practice 'De Molenkreek', Polderdreef 31, 4554 AD, Westdrope, The Netherlands.
⁷ Anacura, Noorwegenstraat 4, 9940, Evergem, Belgium.
⁸ Biometrics Research Group, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, 9820, Merelbeke, Belgium.
⁹ Boehringer Ingelheim Veterinary Medicine Belgium, Noorwegenstraat 4, 9940, Evergem, Belgium. glenn.pauwelyn@boehringer-ingelheim.com.
¹⁰ Boehringer Ingelheim Animal Health, 1730 Olympic Drive, Athens, GA, 30606, USA.

Abstract

Background: As current therapies for canine osteoarthritis (OA) provide mainly symptomatic improvement and fail to address the complex pathology of the disease, mesenchymal stem cells (MSCs) offer a promising biological approach to address both aspects of OA through their immunomodulatory properties.

Methods: This study aimed to investigate the safety and efficacy of xenogeneic MSCs in dogs with OA at different dose levels after intravenous injection. OA was surgically induced in the right stifle joint. Thirty-two male and female dogs were divided into three treatment groups and a control group. Regular general physical examinations; lameness, joint, radiographic, and animal caretaker assessments; pressure plate analyses; and blood analyses were performed over 42 days. At study end, joint tissues were evaluated regarding gross pathology, histopathology, and immunohistochemistry. In a follow-up study, the biodistribution of intravenously injected ^99mTc-labeled equine peripheral blood-derived MSCs was evaluated over 24h in three dogs after the cruciate ligament section.

Results: The dose determination study showed the systemic administration of ePB-MSCs in a canine OA model resulted in an analgesic, anti-inflammatory, and joint tissue protective effect associated with improved clinical signs and improved cartilage structure, as well as a good safety profile. Furthermore, a clear dose effect was found with 0.3 × 10⁶ ePB-MSCs as the most effective dose. In addition, this treatment was demonstrated to home specifically towards the injury zone in a biodistribution study.

Conclusion: This model-based study is the first to confirm the efficacy and safety of systemically administered xenogeneic MSCs in dogs with OA. The systemic administration of a low dose of xenogeneic MSCs could offer a widely accessible, safe, and efficacious treatment to address the complex pathology of canine OA and potentially slow down the disease progression by its joint tissue protective effect.

Keywords: Canine; Equine peripheral blood; Homing; Immunomodulation; Mesenchymal stem cells; Osteoarthritis; Xenogeneic.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Dogs
Female
Follow-Up Studies
Horses
Immunomodulation
Injections, Intra-Articular
Male
Mesenchymal Stem Cell Transplantation* / methods
Mesenchymal Stem Cells*
Osteoarthritis* / pathology
Tissue Distribution