Transforming growth factor beta (TGFβ) signalling is essential for wound healing, including both non-specific scar formation and tissue-specific regeneration. Specific TGFβ isoforms and downstream mediators of canonical and non-canonical signalling play different roles in each of these processes. Here we review the role of TGFβ signalling during tissue repair, with a particular focus on the prototypic isoforms TGFβ1, TGFβ2, and TGFβ3. We begin by introducing TGFβ signalling and then discuss the role of these growth factors and their key downstream signalling mediators in determining the balance between scar formation and tissue regeneration. Next we discuss examples of the pleiotropic roles of TGFβ ligands during cutaneous wound healing and blastema-mediated regeneration, and how inhibition of the canonical signalling pathway (using small molecule inhibitors) blocks regeneration. Finally, we review various TGFβ-targeting therapeutic strategies that hold promise for enhancing tissue repair.

BackgroundIn this study, we examined the association between American Society of Anesthesiologists Physical Status (ASA PS) designation and 48-h mortality for both elective and emergent procedures in a large contemporary dataset (patient encounters between 2009 and 2014) and compared this association with data from a landmark study published by Vacanti et al. in 1970.MethodsPatient history, hospital characteristics, anesthetic approach, surgical procedure, efficiency and quality indicators, and patient outcomes were prospectively collected for 732,704 consecutive patient encounters between January 1, 2009, and December 31, 2014, at 233 anesthetizing locations across 19 facilities in two US states and stored in the Quantum™ Clinical Navigation System (QCNS) database. The outcome (death within 48 h of procedure) was tabulated against ASA PS designations separately for patients with and without “E” status labels. To maintain consistency with the historical cohort from the landmark study performed by Vacanti et al. on adult men at US naval hospitals in 1970, we then created a comparison cohort in the contemporary dataset that consisted of 242,103 adult male patients (with/without E designations) undergoing elective and emergent procedures. Differences in the relationship between ASA PS and 48-h mortality in the historical and contemporary cohorts were assessed for patients undergoing elective and emergent procedures.ResultsAs reported nearly five decades ago, we found a significant trend toward increased mortality with increasing ASA PS for patients undergoing both elective and emergent procedures in a large contemporary cohort (p < 0.0001). Additionally, the overall mortality rate at 48 h was significantly higher among patients undergoing emergent compared to elective procedures in the large contemporary cohort (1.27 versus 0.03 %, p < 0.0001). In the comparative analysis with the historical cohort that focused on adult males, we found the overall 48-h mortality rate was significantly lower among patients undergoing elective procedures in the contemporary cohort (0.05 % now versus 0.24 % in 1970, p < 0.0001) but not significantly lower among those undergoing emergent procedures (1.88 % now versus 1.22 % in 1970, p < 0.0001).ConclusionsThe association between increasing ASA PS designation (1–5) and mortality within 48 h of surgery is significant for patients undergoing both elective and emergent procedures in a contemporary dataset consisting of over 700,000 patient encounters. Emergency surgery was associated with a higher risk of patient death within 48 h of surgery in this contemporary dataset. These data trends are similar to those observed nearly five decades ago in a landmark study evaluating the association between ASA PS and 48-h surgical mortality on adult men at US naval hospitals. When a comparison cohort was created from the contemporary dataset and compared to this landmark historical cohort, the absolute 48-h mortality rate was significantly lower in the contemporary cohort for elective procedures but n...

Introduction: The transforming growth factor beta (TGFβ)/activin signaling pathway has a number of documented roles during wound healing and is increasingly appreciated as an essential component of multi‐tissue regeneration that occurs in amphibians and fish. Among amniotes (reptiles and mammals), less is known due in part to the lack of an appropriate model organism capable of multi‐tissue regeneration. The leopard gecko Eublepharis macularius is able to spontaneously, and repeatedly, regenerate its tail following tail loss. We examined the expression and localization of several key components of the TGFβ/activin signaling pathway during tail regeneration of the leopard gecko. Results: We observed a marked increase in phosphorylated Smad2 expression within the regenerate blastema indicating active TGFβ/activin signaling. Interestingly, during early regeneration, TGFβ1 expression is limited whereas activin‐βA is strongly upregulated. We also observe the expression of EMT transcription factors Snail1 and Snail2 in the blastema. Conclusions: Combined, these observations provide strong support for the importance of different TGFβ ligands during multi‐tissue regeneration and the potential role of TGFβ/activin‐induced EMT programs during this process. Developmental Dynamics 242:886–896, 2013. © 2013 Wiley Periodicals, Inc.

BackgroundWe previously observed that the TGFbeta-Par6 pathway mediates loss of polarity and apoptosis in NMuMG cells. Here we investigate the contribution of Par6 versus TGFbeta receptor I activation to TGFbeta-induced apoptosis in association with changes in apico-basal polarity. We focus on the effect of Par6 activation on alpha6beta4 integrin expression and localization, and Nuclear Factor-kappaB (p65/RelA) activation, previously shown to mediate polarity-dependent cell survival.MethodsUsing immunoblotting and/or immunofluorescence we investigated the effect of TGFbeta1 on apoptosis, alpha6, beta4 and beta1 integrin expression/localization, and p65/RelA phosphorylation/localization in monolayer and three-dimensional (3D) cultures of NMuMG cells with an overactive or inactive Par6 pathway. Results were quantified by band densitometry or as percent of 3D structures displaying a phenotype. Differences among means were compared by two-way ANOVA.ResultsBlocking Par6 activation inhibits TGFbeta-induced apoptosis. Par6 overactivation enhances TGFbeta-induced apoptosis, notably after 6-day exposure to TGFbeta (p < 0.001), a time when parental NMuMG cells no longer respond to TGFbeta apoptotic stimuli. 48-hour TGFbeta treatment reduced beta4 integrin levels in NMuMG monolayers and significantly reduced the basal localization of alpha6 (p < 0.001) and beta4 (p < 0.001) integrin in NMuMG 3D structures, which was dependent on both Par6 and TGFbeta receptor I activation and paralleled apoptotic response. After 6-day exposure to TGFbeta, Par6-dependent changes to beta4 integrin were no longer apparent, but there was reduced phosphorylation of p65/RelA (p < 0.001) only in Par6 overexpressing cells. Differences in p65/RelA localization were not observed among the different cell lines after 48-hour TGFbeta exposure.ConclusionsPar6 and TGFbeta receptor I activation are both necessary for TGFbeta-induced apoptosis in NMuMG cells. Importantly, Par6 overexpression enhances the sensitivity of NMuMG to TGFbeta-induced apoptosis, notably upon prolonged exposure to this growth factor, when NMuMG parental cells are usually apoptosis-resistant. Thus, endogenous Par6 level might be important in determining whether TGFbeta will function as either a pro-apoptotic or pro-survival factor in breast cancer, and potentially aid in predicting patient’s prognosis and therapy response.

Supplemental Digital Content is available in the text