Manufacturing Mesenchymal Stromal Cells for the Treatment of Osteoarthritis in Canine Patients: Challenges and Recommendations

Abstract

The recent interest in advanced biologic therapies in veterinary medicine has opened up opportunities for new treatment modalities with considerable clinical potential. Studies with mesenchymal stromal cells (MSCs) from animal species have focused on in vitro characterization (mostly following protocols developed for human application), experimental testing in controlled studies and clinical use in veterinary patients. The ability of MSCs to interact with the inflammatory environment through immunomodulatory and paracrine mechanisms makes them a good candidate for treatment of inflammatory musculoskeletal conditions in canine species. Analysis of existing data shows promising results in the treatment of canine hip dysplasia, osteoarthritis and rupture of the cranial cruciate ligament in both sport and companion animals. Despite the absence of clear regulatory frameworks for veterinary advanced therapy medicinal products, there has been an increase in the number of commercial cell-based products that are available for clinical applications, and currently the commercial use of veterinary MSC products has outpaced basic research on characterization of the cell product. In the absence of quality standards for MSCs for use in canine patients, their safety, clinical efficacy and production standards are uncertain, leading to a risk of poor product consistency. To deliver high-quality MSC products for veterinary use in the future, there are critical issues that need to be addressed. By translating standards and strategies applied in human MSC manufacturing to products for veterinary use, in a collaborative effort between stem cell scientists and veterinary researchers and surgeons, we hope to facilitate the development of quality standards. We point out critical issues that need to be addressed, including a much higher level of attention to cell characterization, manufacturing standards and release criteria. We provide a set of recommendations that will contribute to the standardization of cell manufacturing methods and better quality assurance.

Keywords: One Health; canine; cell manufacturing; cell therapy; mesenchymal stromal cells; osteoarthritis; quality control criteria.

Figure 1

Therapeutic mechanisms of action of mesenchymal stromal cells. MSCs are defined by their ability for self-renewal, proliferation and undergo tri-lineage differentiation into adipogenic, chondrogenic and osteogenic lineages. They contribute to tissue repair via multiple proposed mechanisms of actions. These include a direct contribution to tissue repair via engraftment and cell differentiation but also immunomodulation of host immune system by counteracting the pro-inflammatory cascades and establishing an anti-inflammatory micro-environment for tissue healing and secretion of extracellular vesicles and soluble factors responsible for intracellular communication with target cells. Treg, regulatory T cell; M1, macrophage type 1; M2, macrophage type 2. Figure created with BioRender.com.

Figure 2

Mesenchymal stromal cells in canine clinical studies. The majority of clinical applications address orthopedic and musculo-skeletal disorders, due to the high incidence of these conditions in dogs coupled with the ease of local administration of MSCs. Clinical trials have also highlighted the local and systemic applications of MSCs for other soft tissue conditions, showing the wide potential of MSC therapies in canine patients. Figure created with BioRender.com.

Figure 3

Overview of the current use of autologous, allogeneic and xenogeneic cells in canine OA clinical studies.

Figure 4

Flow diagram illustrating cell manufacturing stages. The cell manufacturing process starts with tissue sampling at the veterinary clinic. Each stage is critical and is subject to quality control and sterility testing prior to shipment of the final characterized cell product for therapeutic application. In the case of failure of any quality control step, the batch is discarded and in the final stages the sample is retained. Figure created with BioRender.com.