While past studies have suggested that plasticity exists between dermal fibroblasts and adipocytes, it remains unknown whether fat actively contributes to fibrosis in scarring. We show that adipocytes convert to scar-forming fibroblasts in response to Piezo-mediated mechanosensing to drive wound fibrosis. We establish that mechanics alone are sufficient to drive adipocyte-to-fibroblast conversion. By leveraging clonal-lineage-tracing in combination with scRNA-seq, Visium, and CODEX, we define a mechanically naive fibroblast-subpopulation that represents a transcriptionally intermediate state between adipocytes and scar-fibroblasts. Finally, we show that Piezo1 or Piezo2-inhibition yields regenerative healing by preventing adipocytes activation to fibroblasts, in both mouse-wounds and a novel human-xenograft-wound model. Importantly, Piezo1-inhibition induced wound regeneration even in pre-existing established scars, a finding that suggests a role for adipocyte-to-fibroblast transition in wound remodeling, the least-understood phase of wound healing. Adipocyte-to-fibroblast transition may thus represent a therapeutic target for minimizing fibrosis via Piezo-inhibition in organs where fat contributes to fibrosis.

There is undisputable benefit in translating basic science research concretely into clinical practice, and yet, the vast majority of therapies and treatments fail to achieve approval. The rift between basic research and approved treatment continues to grow, and in cases where a drug is granted approval, the average time from initiation of human trials to regulatory marketing authorization spans almost a decade. Albeit with these hurdles, recent research with deferoxamine (DFO) bodes significant promise as a potential treatment for chronic, radiation-induced soft tissue injury. DFO was originally approved by the Food and Drug Administration (FDA) in 1968 for the treatment of iron overload. However, investigators more recently have posited that its angiogenic and antioxidant properties could be beneficial in treating the hypovascular and reactive-oxygen species-rich tissues seen in chronic wounds and radiation-induced fibrosis (RIF). Small animal experiments of various chronic wound and RIF models confirmed that treatment with DFO improved blood flow and collagen ultrastructure. With a well-established safety profile, and now a strong foundation of basic scientific research that supports its potential use in chronic wounds and RIF, we believe that the next steps required for DFO to achieve FDA marketing approval will include large animal studies and, if those prove successful, human clinical trials. Though these milestones remain, the extensive research thus far leaves hope for DFO to bridge the gap between bench and wound clinic in the near future.

Historically believed to be a homogeneous cell type that is often overlooked, fibroblasts are more and more understood to be heterogeneous in nature. Though the mechanisms behind how fibroblasts participate in homeostasis and pathology are just beginning to be understood, these cells are believed to be highly dynamic and play key roles in fibrosis and remodeling. Focusing primarily on fibroblasts within the skin and during wound healing, we describe the field’s current understanding of fibroblast heterogeneity in form and function. From differences due to embryonic origins to anatomical variations, we explore the diverse contributions that fibroblasts have in fibrosis and plasticity. Following this, we describe molecular techniques used in the field to provide deeper insights into subpopulations of fibroblasts and their varied roles in complex processes such as wound healing. Limitations to current work are also discussed, with a focus on future directions that investigators are recommended to take in order to gain a deeper understanding of fibroblast biology and to develop potential targets for translational applications in a clinical setting.

endon injuries are common presentations to hand surgeons. 1 After injury, tendon fibrosis disrupts the tendon matrix leading to complications including rupture and adhesions, which are typically underreported and often require secondary operations. 2 The cause of injury, from sharp lacerations to total crush or avulsion injuries, dictates adhesion formation and functional outcomes. 3 The technique of tendon repair may also impact healing, as atraumatic repairs may reduce fibrosis after surgery. 4 After both acute injury and surgical repairs, inflammation ensues, and edema brings the tendon Background: Fibrosis is a complication of both tendon injuries and repairs. The authors aimed to develop a mouse model to assess tendon fibrosis and to identify an antifibrotic agent capable of overcoming it. Methods: The Achilles tendon of adult C57Bl/6 mice was exposed via skin incision, followed by 50% tendon injury and abrasion with sandpaper. Sham operations were conducted on contralateral hindlimbs. Histologic analyses and immunofluorescent staining for fibrotic markers (collagen type 1 [Col1], α-smooth muscle actin [α-SMA]) were used to confirm that the model induced tendon fibrosis. A second experiment further examined the role of α-SMA in adhesion formation using α-SMA.mTmG mice (6 to 8 weeks old; n = 3) with the same injury model. Lastly, α-SMA.mTmG mice were randomized to either condition 1 (tendon injury [control group]) or condition 2 (tendon injury with galectin-3 inhibitor [Gal3i] treatment at time of injury [treatment group]). Results: Histologic analyses confirmed tendon thickening and collagen deposition after tendon injury and abrasion compared with control. Immunofluorescence showed higher levels of Col1 and α-SMA protein expression after injury compared with sham (P < 0.05). Real-time quantitative polymerase chain reaction also demonstrated increased gene expression of Col1 and α-SMA after injury compared with sham (P < 0.05). Gal3 protein expression also increased after injury and colocalized with α-SMA + fibroblasts surrounding the fibrotic tendon. Gal3i treatment decreased collagen deposition and scarring observed in the treatment group (P < 0.05). Conclusions:The authors' study provides a reproducible and reliable model to investigate tendon fibrosis. Findings suggest the potential of Gal3i to overcome fibrosis resulting from tendon injuries.

Cancer is currently the second leading cause of death in the United States. There is increasing evidence that the tumor microenvironment (TME) is pivotal for tumorigenesis and metastasis. Recently, adipocytes and cancer-associated fibroblasts (CAFs) in the TME have been shown to play a major role in tumorigenesis of different cancers, specifically melanoma. Animal studies have shown that CAFs and adipocytes within the TME help tumors evade the immune system, for example, by releasing chemokines to blunt the effectiveness of the host defense. Although studies have identified that adipocytes and CAFs play a role in tumorigenesis, adipocyte transition to fibroblast within the TME is fairly unknown. This review intends to elucidate the potential that adipocytes may have to transition to fibroblasts and, as part of the TME, a critical role that CAFs may play in affecting the growth and invasion of tumor cells. Future studies that illuminate the function of adipocytes and CAFs in the TME may pave way for new antitumor therapies.