Culture-expanded mesenchymal stromal cell therapy: does it work in knee osteoarthritis? A pathway to clinical success

Abstract

Osteoarthritis (OA) is a degenerative multifactorial disease with concomitant structural, inflammatory, and metabolic changes that fluctuate in a temporal and patient-specific manner. This complexity has contributed to refractory responses to various treatments. MSCs have shown promise as multimodal therapeutics in mitigating OA symptoms and disease progression. Here, we evaluated 15 randomized controlled clinical trials (RCTs) and 11 nonrandomized RCTs using culture-expanded MSCs in the treatment of knee OA, and we found net positive effects of MSCs on mitigating pain and symptoms (improving function in 12/15 RCTs relative to baseline and in 11/15 RCTs relative to control groups at study endpoints) and on cartilage protection and/or repair (18/21 clinical studies). We examined MSC dose, tissue of origin, and autologous vs. allogeneic origins as well as patient clinical phenotype, endotype, age, sex and level of OA severity as key parameters in parsing MSC clinical effectiveness. The relatively small sample size of 610 patients limited the drawing of definitive conclusions. Nonetheless, we noted trends toward moderate to higher doses of MSCs in select OA patient clinical phenotypes mitigating pain and leading to structural improvements or cartilage preservation. Evidence from preclinical studies is supportive of MSC anti-inflammatory and immunomodulatory effects, but additional investigations on immunomodulatory, chondroprotective and other clinical mechanisms of action are needed. We hypothesize that MSC basal immunomodulatory “fitness” correlates with OA treatment efficacy, but this hypothesis needs to be validated in future studies. We conclude with a roadmap articulating the need to match an OA patient subset defined by molecular endotype and clinical phenotype with basally immunomodulatory “fit” or engineered-to-be-fit-for-OA MSCs in well-designed, data-intensive clinical trials to advance the field.

Regenerative medicine for early osteoarthritis

“…Symptomatic improvements in pain and function were reported with minor complications in the majority of studies (12 out of 15 random clinical trials), either autologous or allogenic if not accompanied by notable structural improvement. 25–27 Also, an increase in cartilage volume was demonstrated in some studies. 28,29 Dosage was 3.9 × 10 6 to 150 × 10 6 cells, with moderate to high doses (>40 × 10 6 ) tend to show more effect.…”

“…28,29 Dosage was 3.9 × 10 6 to 150 × 10 6 cells, with moderate to high doses (>40 × 10 6 ) tend to show more effect. 27 Still, currently, there is an absence of large, controlled trials with standardization of cell product manufacturing, and defined target patient populations that are needed to prove the usefulness of cell therapy. In addition, endotypes, combined therapies, and tissue sources can be considered in future studies.…”

Mesenchymal stem cells and their derived exosomes for the treatment of COVID-19

“…Regenerative repair and antifibrotic effects of MSCs: In the context of critical COVID-19 patients, some present with significant alveolar and pulmonary vascular endothelial cell damage, accompanied by varying degrees of pulmonary fibrosis. MSCs promote the repair and regeneration of the damaged alveolar epithelium by secreting multiple cytokines and trophic factors[ 84 , 85 ]. MSCs can restore the function and integrity of damaged alveolar epithelium by secreting paracrine factors such as TGF-α, TGF-β, hepatocyte growth factor (HGF), epithelial growth factor, and angiopoietin 1[ 86 ].…”

Bioadhesive and Injectable Hydrogels and Their Correlation with Mesenchymal Stem Cells Differentiation for Cartilage Repair: A Mini-Review

“…By 2023, 15 randomized controlled clinical trials and 11 nonrandomized RCTs using culture-expanded MSCs in the treatment of knee OA were finished [153]. A total of 179 are ongoing [154], and they suggest net positive effects of MSCs on mitigating pain and symptoms and on cartilage protection and/or repair.…”