PTX-3 Secreted by Intra-Articular-Injected SMUP-Cells Reduces Pain in an Osteoarthritis Rat Model

Abstract

Mesenchymal stem cells (MSCs) are accessible, abundantly available, and capable of regenerating; they have the potential to be developed as therapeutic agents for diseases. However, concerns remain in their further application. In this study, we developed a SMall cell+Ultra Potent+Scale UP cell (SMUP-Cell) platform to improve whole-cell processing, including manufacturing bioreactors and xeno-free solutions for commercialization. To confirm the superiority of SMUP-Cell improvements, we demonstrated that a molecule secreted by SMUP-Cells is capable of polarizing inflammatory macrophages (M1) into their anti-inflammatory phenotype (M2) at the site of injury in a pain-associated osteoarthritis (OA) model. Lipopolysaccharide-stimulated macrophages co-cultured with SMUP-Cells expressed low levels of M1-phenotype markers (CD11b, tumor necrosis factor-α, interleukin-1α, and interleukin-6), but high levels of M2 markers (CD163 and arginase-1). To identify the paracrine action underlying the anti-inflammatory effect of SMUP-Cells, we employed a cytokine array and detected increased levels of pentraxin-related protein-3 (PTX-3). Additionally, PTX-3 mRNA silencing was applied to confirm PTX-3 function. PTX-3 silencing in SMUP-Cells significantly decreased their therapeutic effects against monosodium iodoacetate (MIA)-induced OA. Thus, PTX-3 expression in injected SMUP-Cells, applied as a therapeutic strategy, reduced pain in an OA model.

Role of crosstalk between synovial cells and chondrocytes in osteoarthritis (Review)

“…The cell mixture Nanofat is extracted from AD, and Nanofat conditional medium treatment increased chondrocyte viability and proliferation and reversed the upregulation of the expression of catabolic markers and decreased the expression of synthetic metabolic markers induced by IL-1β ( 120 ). In addition, intra-articular injections of SMUP cells secreted by PTX-3 induced macrophage polarization to an M2 anti-inflammatory phenotype as well as upregulated ARG-1 expression, attenuating osteoarthritic destruction ( 121 ).…”

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

“…Next-generation MSCs, with improved immunomodulatory basal fitness and designed to be fit-for-purpose (for OA treatment), are also being evaluated preclinically and clinically. Small-diameter MSC(CB) grown in hypoxic conditions in calcium-rich medium with improved basal fitness, including the ability to polarize MΦs to proresolving subtypes [ 210 ], are currently being clinically tested in mid-stage OA patients in S. Korea [ 211 ]. Other non-genetic physical modification methods to enhance MSC basal fitness include transient 3D culturing to improve basal immunomodulatory fitness [ 91 ], pulsed electromagnetic field therapy to increase basal MSC chondrogenesis via TGF-β signaling [ 212 , 213 ], and low-level laser therapy-primed MSCs (rev.…”

Role of Mesenchymal Stem Cells and Their Paracrine Mediators in Macrophage Polarization: An Approach to Reduce Inflammation in Osteoarthritis

“…In a recent study, Jin et al created a hypoxic, calcium-rich environment for stem cells to grow while preserving them in a xeno-free, chemically defined cryopreservation media. The paracrine factor PTX-3 generated by these stem cells was shown to remodel M1 macrophages into their anti-inflammatory M2 phenotype in a rat OA model [ 179 ]. Small molecules are also being investigated as a method of priming MSCs due to their unique qualities such as low cost, minuscule size, robust stability, and non-immunogenicity.…”