Hyaluronic acid (HA), a glycosaminoglycan ubiquitous in the skin, has come into the limelight in recent years for its role in facilitating dermal wound healing. Specifically, HA’s length of linearly repeating disaccharides—in other words, its molecular weight (MW)—determines its effects. High molecular weight (HMW)-HA serves an immunosuppressive and anti-inflammatory role, whereas low molecular weight (LMW)-HA contributes to immunostimulation and thus inflammation. During the inflammatory stage of tissue repair, direct and indirect interactions between HA and the innate and adaptive immune systems are of particular interest for their long-lasting impact on wound repair. This review seeks to synthesize the literature on wound healing with a focus on HA’s involvement in the immune subsystems.

Objective: Demonstrate the impact of IL-10 producing T lymphocytes on mediating dermal scarring. Summary Background Data: We demonstrated that CD4⁺ cells are essential to improving postinjury wound healing and preventing fibrosis. CD4⁺ subsets secrete differential cytokine and growth factor profiles, though their role in fibrosis is not known. IL-10, a key anti-inflammatory cytokine shown to promote regenerative wound healing, is secreted by some CD4⁺ subsets. We, therefore, hypothesize that IL-10 producing CD4⁺ T lymphocyte subsets selectively attenuate dermal wound fibrosis. Methods: IL-10^-/- and wild-type murine splenocytes were enriched for CD4⁺ lymphocytes and adoptively transferred into severe combined immunodeficient (SCID) mice that received full-thickness wounds which were analyzed at days 7 and 28 for inflammation and collagen content. We then sorted CD4⁺CD44^int/lowFoxP3^-CD62L⁺ T cells (Tnaive) or CD4⁺CD44^HiFoxP3^- type 1 regulatory (Tr1) T cell subsets from 10BiT murine splenocytes, activated them, and transferred them into wounds. In vitro, dermal fibroblasts were cocultured with Tnaive or Tr1 and the effect on extracellular matrix (ECM) regulation was analyzed. Results: The anti-inflammatory and antifibrotic effects of CD4⁺ cells on SCID wounds were lost with cells from IL-10^-/- mice. Adoptive transfer of Tr1 into SCID mice resulted in accelerated wound closure at d7 with reduced fibrosis at d28, with Tr1 favoring hyaluronan production by fibroblasts, an ECM molecule implicated in IL-10-induced regenerative healing. Conclusions: IL-10 producing T-lymphocytes, specifically Tr1, regulate inflammatory cell cytokine expression to promote HA-rich ECM deposition and attenuate fibrosis. Promoting IL-10 producing lymphocytes in wounds may be a therapeutic target to promote regenerative wound healing.

Renal fibrosis features exaggerated inflammation, extracellular matrix (ECM) deposition, and peritubular capillary loss. We previously showed that IL-10 stimulates high–molecular weight hyaluronan (HMW-HA) expression by fibroblasts, and we hypothesize that HMW-HA attenuates renal fibrosis by reducing inflammation and ECM remodeling. We studied the effects of IL-10 overexpression on HA production and scarring in mouse models of unilateral ureteral obstruction (UUO) and ischemia/reperfusion (I/R) to investigate whether IL-10 antifibrotic effects are HA dependent. C57BL/6J mice were fed with the HA synthesis inhibitor, 4-methylumbelliferone (4-MU), before UUO. We observed that in vivo injury increased intratubular spaces, ECM deposition, and HA expression at day 7 and onward. IL-10 overexpression reduced renal fibrosis in both models, promoted HMW-HA synthesis and stability in UUO, and regulated cell proliferation in I/R. 4-MU inhibited IL-10–driven antifibrotic effects, indicating that HMW-HA is necessary for cytokine-mediated reduction of fibrosis. We also found that IL-10 induces in vitro HMW-HA production by renal fibroblasts via STAT3-dependent upregulation of HA synthase 2. We propose that IL-10–induced HMW-HA synthesis plays cytoprotective and antifibrotic roles in kidney injury, thereby revealing an effective strategy to attenuate renal fibrosis in obstructive and ischemic pathologies.

Discrete subaortic stenosis (DSS) is an obstructive cardiac disease caused by a membranous lesion in the left ventricular (LV) outflow tract (LVOT). Although its etiology is unknown, the higher prevalence of DSS in LVOT anatomies featuring a steep aortoseptal angle (AoSA) suggests a potential role for hemodynamics. Therefore, the objective of this study was to quantify the impact of AoSA steepening on the LV three-dimensional (3D) hemodynamic stress environment. A 3D LV model reconstructed from cardiac cine-magnetic resonance imaging was connected to four LVOT geometrical variations spanning the clinical AoSA range (115°-160°). LV hemodynamic stresses were characterized in terms of cycle-averaged pressure, temporal shear magnitude (TSM), and oscillatory shear index. The wall shear stress (WSS) topological skeleton was further analyzed by computing the scaled divergence of the WSS vector field. AoSA steepening caused an increasingly perturbed subaortic flow marked by LVOT flow skewness and complex 3D secondary flow patterns. These disturbances generated WSS overloads (>45% increase in TSM vs. 160° model) on the inferior LVOT wall, and increased WSS contraction (>66% decrease in WSS divergence vs. 160° model) in regions prone to DSS membrane formation. AoSA steepening generated substantial hemodynamic stress abnormalities in LVOT regions prone to DSS formation. Further studies are needed to assess the possible impact of such mechanical abnormalities on the tissue and cellular responses.