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Abstract
Our understanding of tendon biology continues to evolve, thus leading to opportunities for developing novel, evidence-based effective therapies for the treatment of tendon disorders. Implementing the knowledge of tendon stem/progenitor cells (TSPCs) and assessing their potential in enhancing tendon repair could fill an important gap in this regard. We described different molecular and phenotypic profiles of TSPCs modulated by culture density, as well as their multipotency and secretory activities. Moreover, in the same experimental setting, we evaluated for different responses to inflammatory stimuli mediated by TNFα and IFNγ. We also preliminarily investigated their immunomodulatory activity and their role in regulating degradation of substance P. Our findings indicated that TSPCs cultured at low density (LD) exhibited cobblestone morphology and a reduced propensity to differentiate. A distinctive immunophenotypic profile was also observed with high secretory and promising immunomodulatory responses when primed with TNFα and IFNγ. In contrast, TSPCs cultured at high density (HD) showed a more elongated fibroblast-like morphology, a greater adipogenic differentiation potential, and a higher expression of tendon-related genes with respect to LD. Finally, HD TSPCs showed immunomodulatory potential when primed with TNFα and IFNγ, which was slightly lower than that shown by LD. A shift from low to high culture density during TSPC expansion demonstrated intermediate features confirming the cellular adaptability of TSPCs. Taken together, these experiments allowed us to identify relevant differences in TSPCs based on culture conditions. This ability of TSPCs to acquire distinguished morphology, phenotype, gene expression profile, and functional response advances our current understanding of tendons at a cellular level and suggests responsivity to cues in their in situ microenvironment.
Highlights
Tendon injuries and pathologies are frequently painful and debilitating conditions affecting athletes and nonathletes alike
The shift at passage 1 from low to high density resulted in a cell subset (LDHD) showing a fibroblast-like morphology similar to HD (Figure 2A)
Correlations of CD107a expression and function remain largely unknown in regards to mesenchymal stem cells (MSCs), we recently reported that a high expression of this marker in BMSCs can be attributed to an increased secretory activity, identifying them as “first responder” cells with therapeutically enhanced properties (Bowles et al, 2020)
Summary
Tendon injuries and pathologies are frequently painful and debilitating conditions affecting athletes and nonathletes alike. The role of inflammation that leads to a recruitment of immune cells to the site of the lesion is crucial. The interaction of these cells with tendon cells precedes establishment of an inflammatory amplification loop, which involves multiple alterations of the tissue matrix (Garcia-Melchor et al, 2021). The neural compartment is involved in normal movement of the body. It plays an important role in the pathogenesis of tendinopathy as excessive stimulation leads to neo-innervation together with tissue breakdown and degeneration. Basic research underpinning tendon biology and associated pathologies continues to be pursued to guide our development of novel evidence-based therapies
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