Advances in Mesenchymal Stem cell Therapy for Equine Osteoarthritis

Introduction

Animals, like human beings, undergo aging, an inevitable natural process that affects all living beings. With aging, animals frequently experience the development of articular cartilage lesions, a condition known as osteoarthritis (OA). Sporting and working animals are more likely to develop OA due to the chronic strain they endure, which can lead to damage and deterioration of bone and muscle tissue, resulting in clinical signs [1-3] characterized by chronic pain and increasing disability as a result of progressive joint degeneration [1].

In OA, chondrocytes transition from a quiescent state to an "activated" state, marked by cell proliferation, matrix degradation and remodeling, and inappropriate hypertrophy-like maturation, leading to degradation of the articular cartilage, thickening of the subchondral bone, osteophyte formation, and synovial inflammation. The primary characteristic of OA is the progressive degeneration of articular cartilage and surrounding periarticular tissues.

Unfortunately, due to relative avascularity and therefore the lack of systemic regulation, cartilage has limited intrinsic repair capacity, making regeneration challenging [4]. Therefore, OA is a progressive condition that cannot currently be cured [3]. The absence of a cure for OA requires management strategies to alleviate pain and inflammation, restore normal cartilage and joint function, and prevent further damage [5]. The primary characteristic of OA is the progressive degeneration of articular cartilage and surrounding periarticular tissues. These conditions are primarily associated to either injury, aging or over exertion. After an injury, the affected area of cartilage forms fibrous tissue and loses its structural properties of hyaline tissue. In some cases, the cartilage defect may even penetrate through the entire cartilage to the subchondral bone, resulting in pain, deformity, loss of function of the entire joint, and even disability [6,7]. Similar to humans, horses also experience OA as a result of aging and extended periods of exercise.

As such, animal health is a major concern for the industry, especially in equine, given that the cost of injuries and illnesses in sports animals worldwide amounts to billions of dollars each year. The types and anatomical location of injuries vary among sporting disciplines, levels of competition, and age, but in all cases, articular and musculoskeletal injuries are the most clinically relevant in most sports disciplines, mainly because of their poor healing capacity and the consequent tendency to develop chronic or degenerative disorders [8].

This implies, in a large number of cases, animals are unable to return to training or competition and often must wait for long periods of time to do so. Even in the most severe cases, euthanasia may be necessary [9]. Numerous investigations have shown that orthopedic problems are the main reason for loss of training ability and death in athletic horses [10-13] accounting for more than 70% of lost training days in both jumping and racing horses [14].

Current methods for OA treatment in animals include systemic or intra-articular application of non-steroidal anti-inflammatory drugs (NSAIDs), hyaluronic acid, and other substances [15,16], or even surgical treatment [17]. However, these therapeutic options do not halt the progression of the disease, and always associated with some side effects [18] and at best provide short-term solutions, where the repaired tissue does not have the same characteristics of elasticity and strength as the original tissue, and thus result in a high rate of injury recurrence. In fact, partial healing of the lesion usually ends in fibrosis that is difficult to treat, due to an over-accumulation of extracellular matrix components [19]. This is why veterinary medicine is an active search for therapeutic alternatives that allow the animal to regenerate the damaged tissue, reduce recovery time and improve its overall quality of life.

Stem cells are generally characterized by their capacity for self-renewal and differentiation into different cell types both in vitro and in vivo [20,21]. These cells are responsible for the development and regeneration of an individual's organs and tissues. There are multiple types of stem cells according to their potency levels and the source from which they are obtained. The best known are embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), and mesenchymal stem cells (MSCs). Due to their characteristics, they have become a fundamental tool in regenerative medicine. In recent years, their study and application has grown enormously due to their proven therapeutic action in different pathologies, from tissue damage to degenerative diseases or immune disorders [22].

Unlike ESCs and iPSCs, MSCs are classified as adult stem cells, derived from various tissues of an adult organism, such as skin, adipose tissue, bone marrow, brain, heart, and reproductive organs [23]. The physiological function of these cells in the body is to maintain tissue homeostasis and promote tissue recovery in case of damage, among others [14]. MSCs have a more restricted differentiation potential than pluripotent stem cells, being able to differentiate only to mesoderm-derived cell types [24].

They were first discovered in 1963 and have since been extensively studied [25]. Stem cells have been widely used in clinics and have demonstrated considerable therapeutic value in treating various conditions, including diabetes mellitus [26], OA [27], and macular degeneration [28]. Additionally, stem cell therapy has been utilized in treating animal diseases for many years [29]. In 2003, Smith, et al. applied mesenchymal stem cells (MSCs) to treat superficial flexor tendon injuries in racehorses [30]. This paved the way for the use of stem cells in equine disease treatment, with a focus on osteoarthritic diseases, which is the subject of this review. The aim of the current review article is to provide a clear overview of currently reported equine OA research on MSC application, with a main focus on different sources of MSC. Special attention is given to the distinctive features, differentiation potential for tissues of interest and regeneration outcomes. We aspire to provide valuable insights that can benefit animal health.

MSCs therapy for OA

Given the limitations of current osteoarthritis (OA) management, researchers are exploring new and promising options. Biological therapies utilizing mesenchymal stem cells (MSCs) have emerged as a significant focus in both human and veterinary OA research. Because of their multipotentiality, these adult stem cells have the potential to repopulate cartilage defects. Moreover, MSCs possess immunomodulatory properties that can reduce local and systemic inflammation. Additionally, they release signaling molecules that stimulate local repair cells, potentially aiding in cartilage healing. MSCs also exhibit homing capabilities, enabling them to be recruited to sites of tissue injury, both locally and systemically.

MSCs were first described in 1970 as a population morphologically similar to fibroblasts and with the ability to adhere to plastic. The researchers isolated these cells from bone marrow (naming BM-MSCs) and found that they could later differentiate into osteocytes. Later, it was discovered that MSCs could be isolated from other adult tissues, such as the umbilical cord and placenta. It was then shown that with proper stimulation, these cells could differentiate into various cell types in addition to osteocytes, such as adipocytes and chondrocytes [31]. MSCs are present in various adult tissues, such as bone marrow and adipose tissue, so they can be isolated and cultured in vitro with relative ease [32-34]. However, in most cases, surgical intervention is required to obtain the tissue of which cell will be derived [35]. In addition, MSCs isolated from different tissues show certain differences in their in vitro amplification capacity or differentiation potential, which influences their subsequent applicability [36,37]. Also, besides of the origin from which they are sourced, tissue donor age greatly influences the cell yield obtained from a certain amount of tissue as well as cell proliferation rate. Therefore, the selection of a suitable cell source for clinical use must consider logistical, practical, and functional issues [38]. Currently, MSCs derived from bone marrow and adipose tissue are the most commonly used. Because MSC are nonimmunogenic this makes them a great candidate to be used in both autologous and allogeneic approaches [39-41].

Initially, MSC differentiation and direct incorporation into regenerating tissues were speculated to be a primary mechanism of MSC action; however, the contribution of trans-differentiation and direct incorporation are somewhat controversial [42]. Rather, MSCs were shown to secrete various growth factors and cytokines including interleukin 6 (IL-6), interleukin 1 beta (IL1 β), Tumor necrosis factor alpha (TNF- α), Interleukin 8 (IL-8), Interleukin 10 (IL-10), monocyte chemoattractant protein -1 (MPC-1), vascular cell adhesion molecule (VCAM), Vascular endothelial growth factor (VEGF) and Transforming growth factor β (TGF- β) among others.

Bone Marrow-Derived Mesenchymal Stem Cells (BMSCs)

BMSCs are widely used in veterinary medicine. However, in equines, marrow procurement is usually performed from a sternal puncture [43], a practice that is very risky due to its proximity to the pericardial cavity, and associated risks of serious infection and bleeding [44].

BMSCs are commonly used in equine OA due to their superior chondrogenic differentiation potential compared to adipose tissue-derived MSCs and peripheral blood-derived MSCs [45,46]. Intra-articular injection of BMSCs has been shown to improve cartilage repair quality by increasing aggreging content and tissue strength, as well as facilitating cartilage fracture healing [47]. David, et al. found that intra-articular injection of BMSCs resulted in significantly lower levels of prostaglandin E2 in the synovial fluid compared to the group that received adipose-derived stromal vascular fraction injection in an equine OA model [48]. Additionally, BMSCs are believed to have superior therapeutic effects for OA compared to cord blood MSCs (CB-MSCs) [49,50].

Furthermore, it has been demonstrated that exosomes derived from BMSCs possess therapeutic effects for OA: Hotham and Manon, et al. have reported that vesicles derived from BMSCs can be taken up by autologous chondrocytes and may have anti-inflammatory properties [51]. Numerous preclinical studies in humans have demonstrated that exosomes play a significant role in facilitating information exchange among chondrocytes and modulating the physiological functions of these cells. Due to their complex composition, current research still has a considerable gap in fully understanding the diverse landscape of exosomes derived from various types of mesenchymal stem cells (MSCs) for osteoarthritis (OA) treatment. Among the various contents of exosomes, microRNA (miRNA) has emerged as a primary focus of research and is found in the majority of MSCs. It is worth noting that exosomes derived from certain sources have the ability to sustain cell homeostasis and inhibit cellular apoptosis progression [52-54].

Adipose-Derived Mesenchymal Stem Cells (ADMSCs)

AD-MSCs, derived from equine adipose tissue, offers a safer and more economical alternative to BMSCs, while retaining the same potential for multidirectional differentiation [55]. Due to its ease of collection and abundance of cells present in adipose tissue [56] it has become a preferred choice [57]. AD-MSCs are morphologically and immunophenotypically identical to BMSCs, yet exhibit significantly greater proliferative potential than BMSCs [58,59]. Ad-MSCs have also been shown to be more active in the autocrine production of some growth factors and immunomodulators at equal cell number than BM-MSCs [60,61].

AD-MSCs have been shown to have a therapeutic role in OA. Luis, et al. demonstrated that one or two intra-articular injections of AD-MSCs could reduce lameness in horses with OA and decrease the need for anti-inflammatory medication [62]. The study by Delco, et al. revealed that AD-MSCs with high expression of integrin α10 significantly improved joint damage in horses and activated intra-articular immunomodulation [63]. AD-MSCs can enhance their osteogenic differentiation by binding to macromolecular biomaterials and experiencing fluid shear stress [64].

Embryonic Tissue Mesenchymal Stem Cells

Embryonic tissues, such as umbilical cord blood, placenta, and amniotic membrane [55], are also a rich source of stem cells. These tissues are convenient since normally are discarded after the foal is born. Moreover, they possess a longer survival time attributed to their extended telomerase activity [65, 66]. Stem cells derived from embryonic tissues express markers associated with the embryonic phenotype, thus affording them a broader differentiation capacity [67,68].

Cord blood MSC (CB-MSCs) possess similar potential for treating OA. While BMSCs are frequently used in equine musculoskeletal disorders, it has been suggested that CB-MSCs may have a more robust chondrogenic phenotype. White, et al. demonstrated that CB-MSCs proved to be superior overall in chondrogenic differentiation than BMSCs, with a functionality index >50% of native equine patellar cartilage, as well as collagen production and alkaline phosphatase activity comparable to those of native equine articular cartilage [69]. Additionally, cartilage formed by CB-MSCs has significantly higher chondrogenic differentiation indices than that of the BMSCs source [70].

Mesenchymal Stem Cells from other Tissues

Other tissues, such as peripheral blood and tendon tissue, have been explored for their potential application in equine diseases. Studies have indicated that tendon tissue-derived stem cells demonstrate the ability to differentiate towards osteogenesis and lipogenesis, rendering them promising candidates for osteoarthritis studies [71-73], even better than BMSCs [74]. Due to its ease of procurement, peripheral blood MSCs were considered a good candidate, however their low recovery rated and diminished differentiation potential they are not widely used [46,75]. Furthermore, it has been described that stem cells derived from peripheral blood may not possess the capability to differentiate into chondrocytes [46], thus limiting their potential for treating OA.

Prospective

OA is a prevalent joint disease, particularly among middle-aged and elderly individuals. Equine OA treatment is of particular importance as horses are considered a relevant model for human OA [49] hence all equine research holds great translational promise. MSCs have a promising future in regenerative medicine due to their cellular plasticity. In equine OA, MSC-derived chondrocytes can replace diseased tissue and provide a complete cure, which cannot be achieved through current conventional means such as drug therapy and surgery.

Although both BMSCs and CB-MSCs have shown favorable chondrogenic effects, the advantages and disadvantages of each need to be further explored.

One factor to consider is the availability and accessibility of MSC sources. BMSCs requires invasive procedures such as bone marrow aspiration while CB-MSCs, on the other hand, can be derived from umbilical cord blood, which is a non-invasive and readily available source.

Another consideration is the differentiation potential of MSCs. BMSCs were historically regarded as the preferred treatment for OA due to their robust chondrogenic differentiation capacity. However, in recent years, CB-MSCs have also demonstrated excellent chondrogenic potential, challenging the long-standing dominance of BMSCs in this field.

In addition, the immunomodulatory properties of MSCs should be considered. Originally, their use in cell replacement therapies was considered, i.e., it was thought that by injecting stem cells into a damaged tissue, due to their differentiation potential, cells would differentiate into the specific cell type, thus replacing the damaged tissue [76]. However, it was later shown that the exposure of these cells to a pathological environment did not necessarily allow cells to receive the appropriate signals to carry out a differentiation process to the cell type of interest. MSCs, in particular, were shown to have a beneficial, regenerative effect at the sites of treated [77] and, therefore, other hypotheses about their therapeutic benefits arose. It began to be considered that these cells could play an immunomodulatory role in the inflammatory environment of the wound, or that they could influence the migration and activation of the individual's own cells [78]. Both BMSCs and CB-MSCs have demonstrated immunomodulatory capacity [79,80], which can aid in reducing inflammation and promoting OA tissue repair. However, the specific mechanisms and effects of immunomodulation by these two types of MSCs may differ. Further research and clinical trials are necessary to provide more conclusive evidence and guidance on the selection of MSCs.

Despite the promising therapeutic effects of MSCs and their extracellular vesicles in OA, it is important to be aware of potential complications. Complications following stem cell therapy were observed in horse studies, including swelling, redness, and joint effusion at the injection site, and exacerbations [81,82]. Berglund, et al. demonstrated that recipient horses produced a cytotoxic antibody response after injection of MHC-mismatched MSCs, capable of killing donor MSCs in vitro [83]. Moreover, although not reported in horses, graft-versus-host disease (GVHD) after hematopoietic stem-cell transplantation is possible in dogs [17].

Future research studies employing state-of-the-art technology can be key to validate the effectiveness and safety of MSC therapies and their derivatives allowing these cells to become a leading candidate for the treatment of various diseases, including arthritic diseases.

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