Stem Cell Research and Osteoarthritis

Osteoarthritis is a leading cause of pain and disability. With an aging population its prevalence is even going to increase. Current standard treatments target symptomatic relief rather than the underlying mechanisms and hence prevention. Often conducted surgical interventions are accompanied by significant risks and complications. Lead by an improved understanding of the role of stem cells, their use as a disease modification treatment option comes into focus. Encouraging results from pre-clinical and clinical trials have provided initial evidence of safety and efficacy for many age-, inflammation- or degenerative-related diseases, including osteoarthritis (OA).

The great potential and interest is represented in the increasing numbers of studies on OA treatment using stem cells. The prevailing stem cell type used in OA is mesenchymal stem cells (MSC). MSCs are multipotent progenitor cells with good availability in the body (it can be derived from i.e. bone marrow or fat) that possess self-renewal capability and can differentiate into multiple lineages including osteoblasts (bone buiding cells), adipocytes (fat storing cells) and chondrocytes (cartilage building cells). The count of publications and number of active clinical trials on MSCs is shown in in figure 1.

The primary risk factor for OA is age. Changes in the extracellular matrix (ECM) as well as glycosylation end products accumulations lead to changes in the biomechanical properties and loss of the cartilage`s ability to adapt to mechanical stress.

Chondrocytes within the cartilage matrix exhibit age related changes as well. It has been proposed that reactive oxygen species induced by mechanical or biological stressors may lead to cellular senescence. Cell senescence is currently regarded as probably the single most important factor for aging. But not only senescence itself is responsible for aging: Senescent cells show secretion of Senescent Associated Secretory Phenotype (SASPs). SASPs reduce growth factor response and production and also lead to direct or indirect up regulation of inflammatory cytokine expression (i.e. IL-1, IL-8, IL-6, PEGE2, TNFα, MMP-13). IL-1 and TNFα are primary drivers of a cytokine related degradation of cartilage.

Other processes possibly involved in OA are nitric oxide (inhibition of IGF-1 in chondrocytes) and cytotoxic M1 macrophages as mediators from the synovia (down regulating chondrogenic gene expression of MSCs). Summarized, it is accepted that OA occurs when there exists an imbalance between inflammatory/catabolic and anabolic pathways. Age-related changes lead to the loss of the ability of chondrocytes and tissues within the ECM to maintain a homeostasis between these two pathways. This ultimately leads to cartilage degeneration. The knowledge of catabolic and anabolic imbalance has led to renewed interest in therapies that may be able to influence and encourage maintenance of an appropriate chondral homeostasis.

Methods for the repair of articular cartilage lesions using scaffold transplantation have been investigated successfully in clinical trials. However, these techniques are not easily transferable to OA, where the cartilage loss is rather general then focal.

Pre-clinical and clinical trials with intra-articular injections of MSCs had a favorable outcome regarding both pain and functional improvement. Most importantly, initial studies have shown regrowth of cartilage and disease modifications after MSC treatment. Just as important, systematic reviews have all been in favor of the safety in both -intravascular and intraarticular - injections of MSCs. However, great caution is warranted with culturing and expansion of MSCs. [13]

Mesenchmal Stem Cells StatisticsFigure 1 - Statistics showing the exponential uptake in science and clinical trials on stem cells.

Stem Cell Injection Therapies and Their Effect on Osteoarthritis: Bio-Physiological Perspective

The use of MSCs to repair cartilage tissue was predicated on the hypothesis that these cells could differentiate into chondrocytes and replace the damaged tissue.

While clinical trials with injecting MSCs are ongoing and increasing rapidly, research has evolved both from in-vitro, animal and human experiments, that the effect of tissue regeneration and reduction of inflammation after MSCs is owed to the paracrine activity of the MSCs.

MSCs are often called environmentally-responsive as their secretion varies in response to the local micro environmental cues. Several studies reported, that MSC secretome changes significantly when exposed to inflammatory conditions (i.e. TNFα leads to higher levels of IL-6, IL8 and MCP-1).

This is also the reason why non-pure MSC-sources like Bone Marrow Concentrate (BMC) or mixtures with growth factors from Platelet Rich Plasma (PRP) favored better outcomes compared to pure MSC cultures as they contain synergistic trophic factors. In simple terms: MSC don’t (primarily or at all) differentiate to repair, they communicate to repair. Some of the main pathways involved in OA are shown in figure 2. 



OA changes in Cartilage and Joint Figure 2 - Factors involved in OA [14]

Stem Cell Secretome Paracrine Factors Figure 3 - The general effects of the soluble paracrine factors secreted by MSCs [16].





Stem Cell effect on OA Figure 4 - Simplified effects of some of these factors on osteoarthritis or rheumatoid arthritis-related degenerations [17].

Stem Cell Secretome RA Figure 5 - The more specific pathways of MSCs leading to regenerative effects [17].

The Importance of Paracrine Factors, Extracellular Vesicles and Exosomes: Cellular Medicine Going from Injecting Stem Cells to Understanding Effects to Designing for Results

As mentioned above, efficacy of the autologous or allogeneic MSCs for OA has been demonstrated in animal and human studies. [23-32].

With increasing knowledge, focus has shifted from the final (chondrocyte) differentiation theory to accepting, that a wide range of trophic factors [33] modulate and orchestrate subsequent regeneration processes. These processes include - but are not limited to - proliferation, migration, differentiation and ECM (extracellular matrix) synthesis.

In 2010, tides shifted yet again, as exosomes were reported to be the active agent of MSC against myocardial ischemia reperfusion injury [35]. Previously, Bruno et al attributed the effects of MSC secretion on acute kidney injury to microvesicles [49].

This lead to an explosion of studies as shown in the figure below. New findings explained many of the previously inconsistent observations in stem cell research. Among many other, MSC exosomes were, as expected, reported to mediate cartilage repair and regeneration [36,37]. Interestingly, MSCs from different sources exert similar trophic effects irrespective of the tissue origin and culture conditions [44,45].

Mesenchmal Stem Cells Extracellular Vesicles Exosomes StatisticsFigure 6: Showing the exponentially rising importance of extracellular vesicle in cellular sciences.

While exosomes from healthy MSCs appear to have almost exclusively “wanted” microvesicles and exosomes, in principle, they can also mediate and disseminate injurious signals. For example, the exosomes from cancer cells are a massive research project with both: Potential for new therapeutics but also immediate consequences for new biomarkers. Similarly, exosomes have also found to be involved in the development of OA.

Both microvesicles and exosomes are extracellular vesicles (EVs). They are hypothesized to be a major intercellular communication pathway. They transfer nucleic acids (mRNAs and miRNAs) and proteins between cells to elicit responses in the target cell. This can be complex as the information amount carried can be significant. The main difference between exosomes and microvesicles is the way they are build and released by the (stem) cell. They vary in size: Exosomes are typically between 30-150nm in diameter while microvesicles can have diameters of 100-1000nm.

Mesenchmal Stem Cells Extracellular Vesicles Exosomes Exosomes Knee Repair largeFigure 7: From [83]

Very likely, most immune modulatory responses of cells (change in (epi)genetic expression e.g.) are communicated via exosomes and microvesicles [55]. Hypothetically, this is not limited to immune modulatory responses, but applies to each more complex response of cells. This leaves the trophic factors` impact more like a temporal change in growth behavior but less like a “real immune modulation”. By now databases exist, mapping exosomes and their cargo load of nucleic acids, proteins and lipids. More than 800 gene products and >150 miRNAs have been reported. This database can be accessed via www.exocarta.org. Direct effect of MSC exosomes in humans have been reported to protect against myocardial injury [35], enhance wound healing [70,71], attenuate limb ischemia [69], ameliorate graft-versus-host-disease (GVHD) [72], inhibit pulmonary hypertension [74], alleviate retinal injury [75], reduce renal injury [58], promote hepatic regeneration [73] and improve cartilage and bone regeneration [36,56].

Exosome action on Mesenchymal Stem CellsFigure 8: From [18]

The Anova IRM Approach to OA: Designing for Results

From the research summarized minimalistic above, we are convinced that paracrine factors and especially microvesicles and exosomes hold a potential to cure OA  at some point -  or postpone it by decades.


Our therapeutic approach to OA patients and / or professional athletes therefore always includes either local or systemic injections of lab extracted MSC microvesicles and exosomes. By a proprietary process, we are able to yield an extremely high count of paracrine factors. The count of these extracted microvesicles and exosomes is several orders of magnitude higher than any count of injected MSCs would ever produce in the body.

Employing this Stem Cell Secretome, as we call it, we do not necessarily leave out known effective MSC / BMC-based therapies as well as PRP or senolytic approaches. We rather combine them with our Stem Cell Secretome Therapy, as all these approaches have different primary effects that can be used synergistically. Anova Stem Cell Exosome EV apraochFigure 9 - The Anova-IRM approach: A lab designed process to harvest paracrine factors and Extracellular vesicles at maximum efficiency. This highly potent conditioned media containing billions of EVs can be combined with other therapies [19].

References and Literature - Stem Cell-based Therapies and Osteoarthritis (Click for more)

MSC, BMC, Stem Cell Secretome and EVs

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PRP

Rubio-Azpeitia E, Andia I. Partnership between platelet-rich plasma and mesenchymal stem cells: in vitro experience. Muscles Ligaments Tendons J. 2014;4(1):52–62.

Others

Xu, Ming, et al. "Transplanted senescent cells induce an osteoarthritis-like condition in mice." The Journals of Gerontology Series A: Biological Sciences and Medical Sciences (2016): glw154.

McCulloch, Kendal, Gary J. Litherland, and Taranjit Singh Rai. "Cellular senescence in osteoarthritis pathology." Aging Cell (2017).

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