Therapy free of cells vs human mesenchymal stem cells from umbilical cord stroma to treat the inflammation in OA

Abstract

Osteoarthritis (OA) is closely linked to the increase in the number of senescent cells in joint tissues, and the senescence-associated secretory phenotype (SASP) is implicated in cartilage degradation. In the last decade, extracellular vesicles (EV) in combination with the use of miRNAs to modify post-transcriptional expressions of multiple genes have shown their utility in new therapies to treat inflammatory diseases. This work delves into the anti-inflammatory effect of extracellular vesicles derived from mesenchymal stem cells (MSC) previously modified to inhibit the expression of miR-21. We compare the efficacy of two treatments, MSC with their miR-21 inhibited through lentiviral transfection and their EV, against inflammation in a new OA animal model. The modified MSC and their EV were intraperitoneally injected in an OA animal model twice. One month after treatment, we checked which therapy was the most effective to reduce inflammation compared with animals untreated. Treated OA model sera were analyzed for cytokines and chemokines. Subsequently, different organs were analyzed to validate the results obtained. EV were the most effective treatment to reduce chemokines and cytokines in serum of OA animals as well as SASP, in their organs checked by proteomic and genomic techniques, compared with MSC alone in a statistically significant way. In conclusion, MSC-miR-21−-derived EV showed a higher therapeutic potential in comparison with MSCs-miR-21-. They ameliorate the systemic inflammation through inactivation of ERK1/2 pathway in OA in vivo model. Graphical abstract Workflow of the realization of the animal model of OA by injecting cells into the joint cavity of the left knee of the animals, which produces an increase in serum cytokines and chemokines in the animals in addition to the increase in SASP and markers of inflammation. Inhibition of miR-21 in MSCs, from the stroma of the human umbilical cord, by lentivirus and extraction of their EVs by ultracentrifugation. Finally, application of MSC therapy with its miR-21 inhibited or its EVs produces a decrease in serum cytokines and chemokines in the treated animals, in addition to an increase in SASP and markers of inflammation. The cell-free therapy being the one that produces a greater decrease in the parameters studied

Human umbilical cord mesenchymal stem cells promoting knee joint chondrogenesis for the treatment of knee osteoarthritis: a systematic review

“…EV treatment with mesenchymal stem cells previously modified to contain miR-21 antagonists is more effective at reducing systemic inflammation in age-related diseases than miR-21 in binding HUC-MSCs themselves. In addition, MSC-miR-21-derived EVs can modulate the ERK1/2 family to exert anti-inflammatory effects in the OA model via SDC1 [ 31 ].…”

Effect of miR-21 in mesenchymal stem cells-derived extracellular vesicles behavior

“…SASP has a physiological role inside but acquire additional functions when exposed to the extracellular environment, and they are secreted or displayed by living cells undergoing stress. Arufe et al published that MSC-miR-21 − -derived EV as well as MSCs-miR-21 − improved the systemic inflammation through inactivation of ERK1/2 pathway in OA in vivo model [18]. ERK1/2 is an important messenger for extracellular and intracellular signals, playing a key role in numerous processes, including differentiation, proliferation and cellular senescence [26,33].…”

“…These EVs were found to be more effective in reducing systemic inflammation in age-related diseases such as osteoarthritis (OA) than miR-21-inhibited MSC themselves. In addition, their MSC-miR-21-derived EV modulated the ERK1/2 family to exert its anti-inflammatory effect in the studied in vivo OA model [18].…”

MicroRNA-21a-5p inhibition alleviates systemic sclerosis by targeting STAT3 signaling

“…To create a murine model of SSc, mice received daily subcutaneous injections of 50 µg of bleomycin (BLM, HY-17565A, MedChemExpress) dissolved in 100 µL phosphate-buffered saline (PBS; CBP3071, Dynebio) for 2 weeks. On days 14, 21, and 28 from the start of bleomycin injection, mice were hydrodynamically injected with 100 µg of plasmids containing pre-miRNA-21a-5p (#PMIRH21PA-1) [ 22 ], negative control (pre-miR-NC), anti-sense miR against miRNA-21a-5p (miRZip-21 lentiviral vector expressing anti-sense miRNA-21a-5p, anti-miRNA-21a-5p, #mZIP21-PA-1) [ 23 ] or miRZip-scrambled hairpin vector (scrambled anti-miR, #mZIP000-PA-1) (System Bioscience Inc) in 1 mL saline (n = 5/group). #PMIRH21PA-1 is an expression vector containing the miR-21 precursor construct and #mZIP21-PA-1 represses miR-21.…”