Stem cells and exosomes: a new therapeutic approach for osteoarthritis?

Osteoarthritis (OA) is the most common osteoarticular disease. In most industrialized countries, the direct cost of this condition (hospitalization, surgery, medical consultations, treatment) represents 1% to 2.5% of the gross national product. The indirect costs related to loss of work capacity and income are even higher and likely underestimated. As the prevalence of osteoarthritis increases with age, its cost rises alongside the aging population.

Besides age, predisposing factors include being overweight, metabolic abnormalities often associated with excess weight, joint trauma, skeletal abnormalities/malformations, and heredity.

Osteoarthritis affects all tissues within the joint and is characterized by cartilage deterioration, sclerosis of the bone tissue beneath the cartilage, inflammation of the synovium, calcification of ligaments, and the formation of bone spurs.

Current treatments, aside from prosthetic surgery, mainly focus on symptom relief through anti-inflammatory and pain-relieving medications. These symptomatic treatments do not address the root cause of the disease, and their effectiveness diminishes over time—not to mention the side effects from chronic use. Therefore, it is more than essential to search for new therapeutic strategies.

Human mesenchymal stem cells (MSCs) are multipotent cells capable of self-renewal and differentiation into various cell types such as bone marrow cells, cartilage, tendons, muscles, and even neurons. By differentiating into specialized cells, they play a role in the renewal of aging cells. MSCs are present in all tissues but are primarily isolated from bone marrow, adipose tissue, placenta, or umbilical cord.

MSCs are the most used cells in experimental therapeutic protocols for treating human diseases. For over 20 years, their potential applications in clinical trials have extended to a wide range of conditions, including burn-induced skin lesions, bone repair, vascular regeneration, stroke, autoimmune diseases, and certain retinal disorders.

When administered in humans, MSCs perform several simultaneous functions: they limit inflammation, stimulate the repair of damaged tissues, and modulate the immune response. In osteoarthritis, MSCs are used as a source of regenerative cells that can stimulate the repair of damaged cartilage and reduce local inflammation.

In vitro, when MSCs are co-cultured with chondrocytes (cells responsible for synthesizing the various macromolecules in the cartilage matrix), they enhance the proliferation and protein synthesis capacity of chondrocytes. MSCs also reduce the production of certain pro-inflammatory molecules. Furthermore, they limit the formation of fibrocartilage and osteophytes (excessive bone tissue), which are typical tissue changes seen in osteoarthritis.

In vivo, initial clinical studies on the use of MSCs in joint repair were conducted for treating localized cartilage injuries. Intra-articular injections of MSCs resulted in the formation of reparative tissue at the injury sites. Preclinical studies demonstrated that intra-articular injections of MSCs isolated from adipose tissue could prevent cartilage degeneration and slow the progression of osteoarthritis.

Subsequent clinical studies confirmed the safety and efficacy of MSC injections in reducing pain and improving joint function in patients with knee osteoarthritis (gonarthrosis). In some clinical trials, the beneficial effects lasted up to 12 months post-injection. MRI analyses of the treated joints revealed signs of tissue regeneration in all patients 12 months after their treatment.

Pre-activation of MSCs, for instance, by gamma interferon before implantation, enhances their therapeutic activity, particularly their anti-inflammatory properties. This pre-activation also improves their survival after implantation.

Indeed, injected MSCs do not survive long after implantation, yet their therapeutic effects persist over long-term. This can be explained by the fact that their therapeutic benefits are primarily due to their trophic and anti-inflammatory properties rather than their ability to differentiate into chondrocytes and generate cartilage.

In fact, most functions attributed to MSCs are carried out by vesicles they secrete. These vesicles are categorized into three types based on their size and intracellular formation process: exosomes, microparticles, and apoptotic bodies. These vesicles participate in intercellular communication by delivering various molecules (proteins, lipids, messenger RNAs, microRNAs, etc.) to target cells. The content of exosomes varies depending on the origin of the MSCs, resulting in different effects on the recipient cells with which these vesicles communicate.

The use of exosomes produced by MSCs derived either from adipose tissue or bone marrow represents a new therapeutic approach for degenerative joint diseases such as osteoarthritis.

In vitro, exosomes enhance the production of anabolic factors by osteoarthritic chondrocytes, resulting in the synthesis of reparative tissue. Exosomes also decrease the production of catabolic factors (collagen-degrading matrix metalloproteinases) and inflammatory mediators (oxidative free radicals).

In vivo, exosomes derived from adipose tissue MSCs have demonstrated chondroprotective effects in preclinical trials by reducing the production of inflammatory mediators and increasing the production of anti-inflammatory factors.

The therapeutic efficacy of exosomes can be enhanced by pre-activating the MSCs that produce them in culture. This cellular pre-activation likely alters the composition of the vesicles they produce. For instance, pre-activation of bone marrow-derived MSCs by certain growth factors induces antifibrotic and chondrogenic activity in chondrocytes exposed to exosomes from these pre-activated cells. Modifying the exosome composition through ex vivo pre-treatment of MSCs with various components is a new strategy to enhance their therapeutic potential.