Today I'll point out a review paper that covers a few approaches to stem cell therapy in the context of treating osteoarthritis, a degenerative condition of the joints. Arguably the most demonstrably successful branch of stem cell medicine today is that focused on treating the issues that arise in aging joints: deterioration of tissues, wearing of bone and cartilage, and associated inflammation, pain, and loss of function. The methodologies used for mesenchymal stem cell transplants, developed over the past fifteen to twenty years, today have a good expectation of delivering noticeable improvement to patients. A short turnaround to improvement that is self-evident to the patient is an important component for success in medicine. Therapies that deliver only statistical improvements to function and risk of disease without rapid and obvious physiological improvement from the perspective of the patient - and this category still includes many stem cell therapies for internal organ damage at this point - are a much harder sell at all levels of development.
Stem cell activity declines with age, a reaction to growing levels of cell and tissue damage. This decline is thought to trade off risk of death by cancer on the one hand, the result of damaged cells undertaking more activity, with risk of death due to loss of tissue function on the other hand, the result of stem cells becoming less active and thus delivering fewer replacement cells to the tissues they support. Restoring stem cell populations to their youthful undamaged and active state is a necessary component in any future rejuvenation toolkit. Present day stem cell therapies do not achieve this goal, however. They appear to work largely by altering the local signaling environment for a short period of time, putting existing cells back to work, spurring greater regeneration, and reducing inflammation. The transplanted cells in many cases live only a short time. Most stem cell therapies available today should be viewed as a burst of rebuilding, but rebuilding that uses damaged tools and damaged materials. Nonetheless, even though this is compensation, not rejuvenation, it can result in significantly better patient outcomes than the other presently available options.
Osteoarthritis (OA) is a major cause of disability and chronic pain, characterized by progressive and irreversible cartilage degeneration. The capacity of articular cartilage to repair is inherently poor, with the relative avascularity of cartilage, and hence lack of systemic regulation, likely leading to an ineffective healing and reparative response. With advances in modern medicine improving the prevention, diagnosis and treatment of many diseases that were once life-threatening, the population is now living longer. This increased life expectancy has led to an increased burden of degenerative conditions including osteoarthritis. Current medical treatment strategies for OA are aimed at pain reduction and symptom control rather than disease modification. These pharmaceutical treatments are limited and can have unwanted side effects. The health and economical impact of OA has seen it become an international public health priority and has led to the active exploration and research of alternative regenerative and joint preservation therapies including mesenchymal stem cells.
Whilst both mechanical, genetic and other factors influence development of OA, the primary risk factor is age. Components of the cartilage extracellular matrix (ECM) including type II collagen and proteoglycans undergo age-related structural changes, leading to likely alteration in the biomechanical properties of the ECM. Advanced glycosylation end products also accumulate within cartilage, leading to increased cross-linking and altered biomechanical properties. These changes lead to a loss in the ability of cartilage to adapt to mechanical stress/load. Chondrocytes within the cartilage matrix also exhibit age related changes. It has been proposed that reactive oxygen species (free radicals) induced by mechanical or biological stressors may lead to cell senescence. Cell senescence is accompanied by reduced growth factor response and production, coupled with an observed upregulation of inflammatory cytokine expression. Evidently there are a host of enzymatic compounds that are involved in the disruption of the collagen matrix leading to the degradative process of OA.
Interestingly, evidence indicates that osteoarthritis is associated with a depleted local population of stromal mesenchymal stem cells (MSCs), and those that exist exhibit reduced proliferative and differentiation capacity. The depletion and functional alteration/down regulation of MSC populations with reduced differentiation capacity has also been postulated as a cause for progressive degenerative OA. Despite these findings, it has been noted that there exists MSCs with chondrogenic differentiation potential in patients with OA, irrespective of age or the etiology of disease.
MSCs, due to ease of harvest and isolation with minimal donor site morbidity, coupled with an ability to expand into chondrocytes, have meant that they have been actively explored in regards to tissue engineering and repair. Preclinical trials using techniques similar to autologous harvesting of cartilage from a non-weight bearing area, but substituting chondrocytes with MSCs, have shown positive results with formation of tissue with histological properties consistent with hyaline cartilage and a high type II collagen presence. Others have successfully transplanted isolated MSCs - seeded onto a type I collagen network - to an area of chondral defect, resulting in successful filling of the defect. Later biopsy at two years indicated hyaline like cartilage with type II collagen on histological evaluation.
Recognizing the limitation of biological scaffolds in the treatment of OA - where there exists more diffuse cartilage loss rather than an isolated cartilage lesion - other researchers have sought to assess the effect of intra-articular MSC injections. Preclinical trials have successfully indicated the benefit of MSC intra-articular injections on improvement in function, though results have been inconsistent on cartilage restoration. Some studies, whilst indicating significant pain and functional improvement, have not seen any observable difference in disease progression against controls, whilst others have successfully shown disease modification. Similarly to preclinical results, clinical trials using injectable MSC techniques have reproducibly shown pain and function improvements, though observation of disease modification has been less consistent. Most recently, Phase I and II trials using expanded adipose derived MSCs in the treatment of OA have shown MRI evidence of cartilage regrowth. Following a single intra-articular injection of 100 million MSCs, radiological (MRI) follow-up at 6 months showed increased cartilage volume and histological assessment confirmed hyaline-like cartilage regeneration with the presence of type II collagen.
Despite MSCs being commonly associated with regenerative medicine, and level IV evidence of chondral regrowth and disease modification, there is a paucity of well-controlled trials assessing structural outcome. The reproducible pain and functional improvement seen with MSC injectable therapies, raises the question of whether the biological mechanism of action may be a strong anti-inflammatory effect - including on neurogenic inflammation - rather than regeneration. Further, the observed disease modification in studies that use combination therapy suggests that the efficacy of MSC therapies may be influenced by additional agents including platelet concentrates and hyaluronic acid - though this creates a further layer of confusion regarding cause and effect. Nonetheless, MSC based cell therapies offer an exciting possibility in the treatment of OA and importantly show promise in disease modification, with potential inhibition of progression and recent evidence of reversal of this degenerative process.