Updates on mesenchymal stem cell therapies for articular cartilage regeneration in large animal models

Abstract

There is an unmet need for novel and efficacious therapeutics for regenerating injured articular cartilage in progressive osteoarthritis (OA) and/or trauma. Mesenchymal stem cells (MSCs) are particularly promising for their chondrogenic differentiation, local healing environment modulation, and tissue- and organism-specific activity; however, despite early in vivo success, MSCs require further investigation in highly-translatable models prior to disseminated clinical usage. Large animal models, such as canine, porcine, ruminant, and equine models, are particularly valuable for studying allogenic and xenogenic human MSCs in a human-like osteochondral microenvironment, and thus play a critical role in identifying promising approaches for subsequent clinical investigation. In this mini-review, we focus on [1] considerations for MSC-harnessing studies in each large animal model, [2] source tissues and organisms of MSCs for large animal studies, and [3] tissue engineering strategies for optimizing MSC-based cartilage regeneration in large animal models, with a focus on research published within the last 5 years. We also highlight the dearth of standard assessments and protocols regarding several crucial aspects of MSC-harnessing cartilage regeneration in large animal models, and call for further research to maximize the translatability of future MSC findings.

Systematic review and meta-analysis of positive long-term effects after intra-articular administration of orthobiologic therapeutics in horses with naturally occurring osteoarthritis

“…First, horses spontaneously develop chondral defects and age-/trauma-induced OA that are very similar to humans (15). Second, there are numerous in vitro and in vivo studies, some even with experimentally induced OA, in which the therapeutic index of orthobiologic therapeutics can be assessed (109).…”

Immunomodulatory Mechanisms and Therapeutic Potential of Mesenchymal Stem Cells

“…In comparison, HUC-MSCs have shown a minimal response to the allogeneic immune risk in vivo, regarding HUC-MSCs as a suitable therapeutic candidate [72]. Some reports also found that xenogenic human MSCs have the potential to display positive ability in mouse tumor diseases, sheep tibia bone defect, porcine osteochondral reconstitution, and cartilage regeneration in canines [73][74][75]. Xenogenic human MSCs with lower weakly immunogenicity possess the therapeutic potential in preclinical and clincal studies.…”

Cellular modifications and biomaterial design to improve mesenchymal stem cell transplantation

“…160 Each method of delivery has its advantages and disadvantages, and both have been explored to repair a wide range of tissues including heart, cartilage, bone, and tendon. 165–168 For example, in the treatment of myocardial infarction, injectable biomaterials are more commonly used to deliver MSCs to the intramyocardial space due to the relative accessibility of this approach. Alternatively, implantable cardiac patches can also be applied to deliver MSCs proximally to injured tissue.…”

“…Furthermore, homing of PEDF-transduced MSCs to primary tumors suppresses tumor growth and metastasis, resulting in better therapeutic outcomes. 123 Chen and coworkers (2021) transplanted adenovirally-transduced VEGF 165 -expressing MSCs in a rat model of acute liver failure, and reported enhanced multipotency and increased homing and colonization of cells in liver tissue. 124 Likewise, MSCs, which have been modified to express growth differentiation factor 11 (GDF11) and maintained in hypoxia, display reduced cellular apoptosis, increased paracrine effects and preserved mitochondrial function.…”