Cell non-autonomous functions of S100a4 drive fibrotic tendon healing

Abstract

Identification of pro-regenerative approaches to improve tendon healing is critically important as the fibrotic healing response impairs physical function. In the present study we tested the hypothesis that S100a4 haploinsufficiency or inhibition of S100a4 signaling improves tendon function following acute injury and surgical repair in a murine model. We demonstrate that S100a4 drives fibrotic tendon healing primarily through a cell non-autonomous process, with S100a4 haploinsufficiency promoting regenerative tendon healing. Moreover, inhibition of S100a4 signaling via antagonism of its putative receptor, RAGE, also decreases scar formation. Mechanistically, S100a4 haploinsufficiency decreases myofibroblast and macrophage content at the site of injury, with both cell populations being key drivers of fibrotic progression. Moreover, S100a4-lineage cells become α-SMA+ myofibroblasts, via loss of S100a4 expression. Using a combination of genetic mouse models, small molecule inhibitors and in vitro studies we have defined S100a4 as a novel, promising therapeutic candidate to improve tendon function after acute injury.

S100A4 Silencing Facilitates Corneal Wound Healing After Alkali Burns by Promoting Autophagy via Blocking the PI3K/Akt/mTOR Signaling Pathway

“… 31 Deficiency of S100A4 leads to the alteration of S100A4-lineage cells toward ɑ-SMA + myofibroblasts, driving the promotion of tendon function after acute injury and surgical repair. 32 Ectopic expression of S100A4 has been reported to be implicated in some inflammatory diseases such as airway inflammation in asthma. 33 Knockout of S100A4 in mice dampens the release of proinflammatory cytokines such as TNF-α, IL-6, and IL-17 and thus results in reduction in colon inflammation.…”

The cellular basis of fibrotic tendon healing: challenges and opportunities

“…In contrast, knock-down of S100a4 expression promotes regenerative tendon healing, including improvements in both range of motion and mechanical properties. Furthermore, these mice healing with decreases in macrophage and myofibroblast content, consistent with a more regenerative environment (106). However, the origin(s) of S100a4+ cells during healing, and the specific contributions of intrinsic vs. extrinsically derived S100a4+ cells are unclear.…”

“…Combined, these studies indicate that the localization of Scx-expressing cells is likely tendon-, context-, and time-dependent. In addition to Scx, we have recently shown that the small calcium binding protein S100a4 is expressed by many tendon cells during homeostasis, and both S100a4+ and S100a4-lineage cells are found within the bridging scar tissue during tendon healing (105,106). Functionally, depletion of proliferating S100a4+ cells impairs restoration of mechanical properties following injury.…”

“…This suggests that Scx-lineage cells are not the primary source of αSMA+ cells in healing tendon but that αSMA-lineage cells can express Scx in response to injury. We have recently shown that a subset of S100a4-lineage cells become αSMA+ following tendon injury while actively expressing S100a4+ cells do not co-express αSMA, indicating that some S100a4-lineage cells turn off S100a4 during the transition to myofibroblasts following tendon repair (106). Moreover, myofibroblastic cells have been noted in the scar tissue of naturally occurring equine flexor tendon injuries along with substantially increased levels of collagen type III (112), suggesting that these cells are somehow involved in maintaining the scar tissue, whether it is by actively producing the fibrotic ECM or by inhibiting the migration of other cell types.…”

Bringing tendon biology to heel: Leveraging mechanisms of tendon development, healing, and regeneration to advance therapeutic strategies

“…A separate study from the same group also demonstrated that the fibrosispromoting factor S100 calcium binding protein A4 (S100a4) is expressed in resident tenocytes and that these cells also contribute to the formation of scar tissue following FDL repair. 143 Lineage tracing of both populations following FDL repair intriguingly revealed largely separate contributions to the scar tissue, with Scx + tenocytes mainly contributing to the aligned bridging tendon tissue and S100a4 + tenocytes comprising the majority of neighboring fibrotic tissue ( Figure 3A). Ackermann et al 143 further found that S100a4haploinsufficiency and S100a4-expressing cell ablation during FDL repair improved tendon healing outcomes.…”