Search

Background: Women with cosmetic implants have lower rates of future breast cancer than the general population. We hypothesized the implant foreign body response could induce a local protective anti-cancer immunosurveillance. We expanded on our previous finding which showed women with breast implants have elevated antibody responses to certain breast cancer proteins., Methods: Blood samples and breast tissue were collected from women undergoing first time breast augmentation (implant-naive, IN) and revision breast augmentation (implant-exposed, IE). Sera were collected and antibody levels to common breast cancer proteins were quantified by enzyme-linked immunosorbent assay (ELISA). RT-PCR was performed on breast tissue samples to quantify immune-related gene expression levels between IN and IE. Bulk RNA sequencing was performed to identify differentially expressed genes and altered signaling pathways in the breasts of IN versus IE., Results: In total, 188 patients were recruited (117 IN, 71 IE). Data demonstrated that IE patients had higher levels of antibodies to MUC-1, ER, and mammaglobin A compared to IN patients. MUC-1 expression was found to be higher in IE compared to IN breast tissue. RNA-seq analysis demonstrated upregulated pathways in IE breast tissue for B cell activation and development, Th2 related genes, T cell activation, chemotactic factors, and responses to estrogen., Conclusion: This is the first study to demonstrate that peri-implant inflammation extends beyond the implant capsule to breast parenchyma. Women with breast implants have more activated B cells in the breast parenchyma and elevated antibody responses to breast cancer antigen., Competing Interests: Statement of Financial Disclosures, Conflicts of Interest, and Products: Sophia Allison, BA has no financial disclosures of conflicts of interest David Dolivo, PhD has no financial disclosures of conflicts of interest Puja Jagasia, BA has no financial disclosures of conflicts of interest Kristine Gargiulo, BS has no financial disclosures of conflicts of interest Shreya Battu, BS has no financial disclosures of conflicts of interest Seok Jong Hong, PhD has no financial disclosures of conflicts of interest Irene Helenowski, PhD has no financial disclosures of conflicts of interest, (Copyright © 2024 by the American Society of Plastic Surgeons.)

Fibrosis is a ubiquitous pathology, and prior studies have indicated that various artemisinin (ART) derivatives (including artesunate (AS), artemether (AM), and dihydroartemisinin (DHA)) can reduce fibrosis in vitro and in vivo. The medicinal plant Artemisia annua L. is the natural source of ART and is widely used, especially in underdeveloped countries, to treat a variety of diseases including malaria. A. afra contains no ART but is also antimalarial. Using human dermal fibroblasts (CRL-2097), we compared the effects of A. annua and A. afra tea infusions, ART, AS, AM, DHA, and a liver metabolite of ART, deoxyART (dART), on fibroblast viability and expression of key fibrotic marker genes after 1 and 4 days of treatment. AS, DHA, and Artemisia teas reduced fibroblast viability 4 d post-treatment in up to 80% of their respective controls. After 4 d of treatment, AS DHA and Artemisia teas downregulated ACTA2 up to 10 fold while ART had no significant effect, and AM increased viability by 10%. MMP1 and MMP3 were upregulated by AS, 17.5 and 32.6 fold, respectively, and by DHA, 8 and 51.8 fold, respectively. ART had no effect, but A. annua and A. afra teas increased MMP3 5 and 16-fold, respectively. Although A. afra tea increased COL3A1 5 fold, MMP1 decreased >7 fold with no change in either transcript by A. annua tea. Although A. annua contains ART, it had a significantly greater anti-fibrotic effect than ART alone but was less effective than A. afra . Immunofluorescent staining for smooth-muscle α-actin (α-SMA) correlated well with the transcriptional responses of drug-treated fibroblasts. Together, proliferation, qPCR, and immunofluorescence results show that treatment with ART, AS, DHA, and the two Artemisia teas yield differing responses, including those related to fibrosis, in human dermal fibroblasts, with evidence also of remodeling of fibrotic ECM.

Chronic or delayed healing wounds constitute an ever-increasing burden on healthcare providers and patients alike. Thus, therapeutic modalities that are tailored to particular deficiencies in the delayed wound healing response are of critical importance to improve clinical outcomes. Human amnion-derived viable and devitalized allografts have demonstrated clinical efficacy in promoting the closure of delayed healing wounds, but the mechanisms responsible for this efficacy and the specific wound healing processes modulated by these tissues are not fully understood. Here, we utilized a diabetic murine excisional wound model in which healing is driven by granulation and re-epithelialization, and we applied viable (vHAMA) or devitalized (dHAMA) amnion-derived allografts to the wound bed in order to determine their effects on wound healing processes. Compared to control wounds that were allowed to heal in the absence of treatment, wounds to which vHAMA or dHAMA were applied demonstrated enhanced deposition of granulation tissue accompanied by increased cellular proliferation and increased de novo angiogenesis, while vHAMA-treated wounds also demonstrated accelerated re-epithelialization. Taken together, these data suggest that both vHAMA and dHAMA facilitate wound healing through promoting processes critical to granulation tissue formation. Further understanding of the cellular and tissue mechanisms underlying the effects of tissue-derived matrices on wound healing will enable tailored prescription of their use in order to maximize clinical benefit., (© 2022 The Authors. Clinical and Experimental Pharmacology and Physiology published by John Wiley & Sons Australia, Ltd.)

Background: Hypertrophic scars (HTS) result from injury to the skin and represent a clinical burden with limited treatment options. Previously, we demonstrated that statin drugs could attenuate HTS formation, but convenient topical delivery and retention of these drugs at the wound site remains a challenge., Aims: Here, we aimed to develop a topical cream formulation that can deliver statin drugs simply and conveniently to reduce scar hypertrophy., Methods: We formulated creams containing 10% pravastatin, 2% simvastatin, and 10% simvastatin. We tested these creams for their ability to reduce scar hypertrophy and attenuate dermal fibrosis in a clinically relevant HTS wound model performed in rabbit ear skin. We also monitored trans-epidermal water loss (TEWL) over the course of wound healing in order to understand the effects of statin treatment on epidermal barrier recovery., Results: Of the three creams formulated, only application of 10% simvastatin cream significantly attenuated hypertrophy of resultant scars compared with vehicle cream application. Application of 10% simvastatin cream resulted in a decrease in macrophage and myofibroblast density at post-operative day 28 (POD28) harvest. Application of 10% simvastatin cream resulted in visible symptoms of dryness and increased TEWL at POD28, but subsequent withdrawal of statin cream treatment resulted in rapid alleviation of dryness and decrease in TEWL back to normal levels., Conclusions: Our data demonstrate that topical administration of 10% simvastatin cream antagonizes dermal fibrosis and reduces hypertrophy in an HTS model, and withdrawal of the cream enables recovery of epidermal barrier and resolution of skin dryness., (© 2022 The Authors. Journal of Cosmetic Dermatology published by Wiley Periodicals LLC.)

Damage to epidermis results in loss of barrier function and resultant pathological inflammatory signaling, triggering further damage to the skin. Here we investigate transcriptomic datasets generated from varied skin pathologies associated with disrupted epidermis and pinpoint CD14/S100 signaling as a conserved pathway upregulated in dermatopathologies characterized by a compromised epidermal barrier. We show that dermatitic and fibrotic tissues of humans and mouse models, which are associated with compromised epidermal barrier, demonstrate upregulation of CD14 and S100 proteins, damage-associated molecular patterns (DAMPs), in the epidermis. In vitro stratified keratinocyte cultures exposed to reduced hydration conditions show upregulated CD14/S100 family genes and pro-inflammatory gene expression, as well as decreased barrier gene expression. Knockdown and overexpression of CD14 in stratified keratinocyte cultures suppresses and induces expression, respectively, of S100 family genes and CXCL8. Taken together, these data suggest that upregulation of CD14 and/or S100 family genes in pathological epidermis results in potentiated inflammatory signaling, leading to diminished epidermal barrier function that may yield further inflammation. Future strategies to target CD14 may be utilized to dampen the response to epithelial injury for conditions of the skin and other organs., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Infection is a major source of complications in delayed diabetic wound healing. Increased understanding of differential bacterial responses to diabetic wounds will enable us to better understand chronic wound pathogenesis. Here we create delayed-healing wounds infected with Staphylococcus aureus in non-diabetic and diabetic mice and used RNA-seq to compare bacterial gene expression profiles 3 or 7 days after infection. Analysis at day 3 demonstrated substantial transcriptomic differences between bacteria colonising non-diabetic and diabetic wound beds. Most of these transcriptional differences resolved by day 7, suggesting normalisation of many bacterial phenotypes later in the diabetic wound healing process. Lingering differentially expressed genes at day 7 were enriched for genes related to carbohydrate metabolism, which includes genes of the lac operon, and capsular polysaccharide synthesis, which includes the cap8 locus. These data encourage further research into host-pathogen interactions in wound healing and how they influence differential outcomes in the diabetic wound environment., (© 2022 The Authors. Wound Repair and Regeneration published by Wiley Periodicals LLC on behalf of The Wound Healing Society.)

Significance: Scar formation is a natural result of mammalian wound healing. In humans and other mammals, however, deep dermal wounds and thermal injuries often result in formation of hypertrophic scars, leading to substantial morbidity and lending great importance to development of therapeutic modalities for burn scars. Clinical Issues: Thus, preclinical burn wound models that adequately simulate processes underlying human burn-induced wound healing, particularly those processes leading to chronic inflammation and development of hypertrophic scars, are critical to developing further treatment paradigms for clinical use. Approach: In this study, we review literature describing various burn models, focusing on their characteristics and the functional readouts that lead to generation of useful data. We also briefly discuss recent work using human ex vivo skin culture as an alternative to animal models, as well as our own development of rabbit ear wound models for burn scars, and assess the pros and cons of these models compared to other models. Future Direction: Understanding of the strengths and weaknesses of preclinical burn wound models will enable choice of the most appropriate wound model to answer particular clinically relevant questions, furthering research aimed at treating burn scars.

Background Aims: The treatment and care of human wounds represent an enormous burden on the medical system and patients alike. Chronic or delayed healing wounds are characterized by the inability to form proper granulation tissue, followed by deficiencies in keratinocyte migration and wound re-epithelialization, leading to increased likelihood of infection and poor wound outcomes. Human reticular acellular dermal matrix (HR-ADM) is one type of tissue graft developed to enhance closure of delayed healing wounds that has demonstrated clinical utility through accelerating closure of lower extremity diabetic ulcers, but the mechanisms underlying this clinical success are not well understood., Methods: The authors utilized a diabetic murine splinted excisional wound model to investigate the effects of HR-ADM application on wound closure., Results: The authors demonstrate that application of HR-ADM served as a dermal scaffold and promoted rapid re-epithelialization and keratinocyte proliferation, resulting in accelerated wound closure while minimizing granulation tissue formation. HR-ADM-applied wounds also demonstrated evidence of cellular infiltration, neovascularization and collagen remodeling by the host organism., Conclusions: These data suggest that HR-ADM supports epidermal closure in delayed healing wounds and remodeling of the matrix into host tissue, lending further support to the clinical success of HR-ADM described in clinical reports., Competing Interests: Declaration of Competing Interest AP is an employee of MTF Biologics, the company that processes and distributes the AlloPatch membrane. RG is a consultant for MTF Biologics. All other authors have no commercial, proprietary or financial interest in the products or companies described in this article., (Copyright © 2020 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)

Background: Women with cosmetic breast implants have significantly lower rates of subsequent breast cancer than the general population (relative risk, 0.63; 95 percent CI, 0.56 to 0.71). The authors hypothesize that breast implant-induced local inflammation stimulates immunosurveillance recognition of breast tumor antigen., Methods: Sera were collected from two cohorts of healthy women: women with long-term breast implants (i.e., breast implants for >6 months) and breast implant-naive women. Antibody responses to breast tumor antigens were tested by enzyme-linked immunosorbent assay and compared between cohorts by unpaired t test. Of the implant-naive cohort, nine women underwent breast augmentation, and antibody responses before and after implant placement were compared by paired t test., Results: Sera were collected from 104 women: 36 (34.6 percent) long-term breast implants and 68 (65.4 percent) implant-naive women. Women with long-term breast implants had higher antibody responses than implant-naive women to mammaglobin-A (optical density at 450 nm, 0.33 versus 0.22; p = 0.003) and mucin-1 (optical density at 450 nm, 0.42 versus 0.34; p = 0.02). There was no difference in antibody responses to breast cancer susceptibility gene 2, carcinoembryonic antigen, human epidermal growth factor receptor-2, or tetanus. Nine women with longitudinal samples preoperatively and 1 month postoperatively demonstrated significantly elevated antibody responses following implant placement to mammaglobin-A (mean difference, 0.13; p = 0.0002) and mucin-1 (mean difference 0.08; p = 0.02). There was no difference in postimplant responses to other breast tumor antigens, or tetanus., Conclusions: Women with long-term breast implants have higher antibody recognition of mammaglobin-A and mucin-1. This study provides the first evidence of implant-related immune responses to breast cancer antigens., Clinical Question/level of Evidence: Therapeutic, V., (Copyright © 2021 by the American Society of Plastic Surgeons.)

Within an articulately characterized family of ion channels, the voltage-gated sodium channels, exists a black sheep, SCN7A (Na x ). Na x , in contrast to members of its molecular family, has lost its voltage-gated character and instead rapidly evolved a new function as a concentration-dependent sensor of extracellular sodium ions and subsequent signal transducer. As it deviates fundamentally in function from the rest of its family, and since the bulk of the impressive body of literature elucidating the pathology and biochemistry of voltage-gated sodium channels has been performed in nervous tissue, reports of Na x expression and function have been sparse. Here, we investigate available reports surrounding expression and potential roles for Na x activity outside of nervous tissue. With these studies as justification, we propose that Na x likely acts as an early sensor that detects loss of tissue homeostasis through the pathological accumulation of extracellular sodium and/or through endothelin signaling. Sensation of homeostatic aberration via Na x then proceeds to induce pathological tissue phenotypes via promotion of pro-inflammatory and pro-fibrotic responses, induced through direct regulation of gene expression or through the generation of secondary signaling molecules, such as lactate, that can operate in an autocrine or paracrine fashion. We hope that our synthesis of much of the literature investigating this understudied protein will inspire more research into Na x not simply as a biochemical oddity, but also as a potential pathophysiological regulator and therapeutic target.

Since chronic, non-healing wounds represent an increasing source of economic and temporal burden for patients who suffer from them and healthcare professionals that treat them, therapeutic modalities that promote closure of delayed and non-healing wounds are of utmost importance. Recent clinical results of allografts derived from amnion and chorion placental layers encourage further investigation of the mechanisms underlying clinical efficacy of these products for treatment of wounds. Here, we utilized a diabetic murine splinted excisional wound model to investigate the effects of a dehydrated human amnion/chorion-derived allograft (dHACA) on delayed wound healing, as well as the effects of dehydrated allograft derived solely from amnion tissue of the same donor. We examined wound healing by histological endpoint analysis, and we assessed other parameters relevant to functional wound healing in the wound bed including angiogenesis, macrophage phenotypes, proliferative activity, and gene expression. Herein we demonstrate that application of dHACA to a murine diabetic model of delayed wound progression results in better macroscale wound resolution outcomes, including rate of closure, compared to unaided wound progression, while dehydrated human amnion allograft (dHAA) fails to improve outcomes. Improved gross wound resolution observed with dHACA was accompanied by increased granulation tissue formation, proliferation and vascular ingrowth observed in the wound bed, early macrophage polarization towards anti-inflammatory phenotypes, and downregulation of pro-fibrotic gene expression. Overall, our data suggest that improvements in the rates of delayed wound closure observed from combined amnion/chorion allografts are associated with modulation of critical cellular and tissue processes commonly found to be dysregulated in delayed healing wounds, including proliferation, vascularization, inflammation, and re-epithelialization., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Mammalian wound healing is a carefully orchestrated process in which many cellular and molecular effectors respond in concert to perturbed tissue homeostasis in order to close the wound and re-establish the skin barrier. The roles of many of these molecular effectors, however, are not entirely understood. Our lab previously demonstrated that the atypical sodium channel Na x (encoded by Scn7a) responds to wound-induced epidermal dehydration, resulting in molecular cascades that drive pro-inflammatory signaling. Acute inhibition of Na x was sufficient to attenuate dermatopathological symptoms in models of hypertrophic scar and dermatitis. To date, however, the role of Na x in excisional wound healing has not been demonstrated. Here we report development of a knockout mouse that lacks expression of functional Na x , and we demonstrate that lack of functional Na x results in deficient wound healing in a murine splinted excisional wound healing model. This deficiency in wound healing was reflected in impaired re-epithelialization and decreased keratinocyte proliferation, a finding which was further supported by decreased proliferation upon Na x knockdown in HaCaT cells in vitro. Defective wound healing was observed alongside increased expression of inflammatory genes in the wound epidermis of Na x -/- mice, suggesting that mice lacking functional Na x retain the ability to undergo skin inflammation. Our observations here motivate further investigation into the roles of Na x in wound healing and other skin processes., (© 2020 by the Wound Healing Society.)

Fibrosis is a pathological reparative process that can occur in most organs and is responsible for nearly half of deaths in the developed world. Despite considerable research, few therapies have proven effective and been approved clinically for treatment of fibrosis. Artemisinin compounds are best known as antimalarial therapeutics, but they also demonstrate antiparasitic, antibacterial, anticancer, and anti-fibrotic effects. Here we summarize literature describing anti-fibrotic effects of artemisinin compounds in in vivo and in vitro models of tissue fibrosis, and we describe the likely mechanisms by which artemisinin compounds appear to inhibit cellular and tissue processes that lead to fibrosis. To consider alternative routes of administration of artemisinin for treatment of internal organ fibrosis, we also discuss the potential for more direct oral delivery of Artemisia plant material to enhance bioavailability and efficacy of artemisinin compared to administration of purified artemisinin drugs at comparable doses. It is our hope that greater understanding of the broad anti-fibrotic effects of artemisinin drugs will enable and promote their use as therapeutics for treatment of fibrotic diseases., (© 2021 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.)

Background: Skeletal muscle trauma can produce grave functional deficits, but therapeutic options remain limited. The authors studied whether a decellularized skeletal muscle scaffold would provide benefits in inducing skeletal muscle regeneration over acellular dermal matrices., Methods: Eighty-two rat muscle defects were surgically created and assigned to no intervention or implantation of AlloDerm, Strattice, decellularized rat muscle, or decellularized rat dermis to 30 or 60 days. Decellularized rat muscle and dermis were prepared using a negative pressure-assisted protocol. Assessment for cellularity, neovascularization, myogenesis, inflammation and fibrosis were done histologically and by polymerase chain reaction., Results: Histology showed relative hypercellularity of AlloDerm (p < 0.003); Strattice appeared encapsulated. Immunofluorescence for CD31 and myosin heavy chain in decellularized rat muscle revealed dense microvasculature and peripheral islands of myogenesis. MyoD expression in muscle scaffolds was 23-fold higher than in controls (p < 0.01). Decellularized rat muscle showed no up-regulation of COX-2 (p < 0.05), with less expression than decellularized rat dermis and Strattice (p < 0.002). Decellularized rat muscle scaffolds expressed tumor necrosis factor-α less than Strattice, AlloDerm, and decellularized rat dermis (p < 0.01); collagen-1a less than decellularized rat dermis and Strattice (p < 0.04); α-smooth muscle actin 7-fold less than AlloDerm (p = 0.04); and connective tissue growth factor less than Strattice, AlloDerm, and decellularized rat dermis (p < 0.02)., Conclusion: Decellularized muscle matrix appears to reduce inflammation and fibrosis in an animal muscle defect as compared with dermal matrices and promotes greater expression of myocyte differentiation-inducing genes.

Cell-derived matrices (CDMs) provide an exogenous source of human extracellular matrix (ECM), with applications as cell delivery vehicles, substrate coatings for cell attachment and differentiation, and as biomaterial scaffolds. However, commercial application of CDMs has been hindered due to the prolonged culture time required for sufficient ECM accumulation. One approach to increasing matrix deposition in vitro is macromolecular crowding (MMC), which is a biophysical phenomenon that limits the diffusion of ECM precursor proteins, resulting in increased ECM accumulation at the cell layer. Hyaluronic acid (HA), a natural MMC highly expressed in vivo during fetal development, has been shown to play a role in ECM production, but has not been investigated as a macromolecule for increasing cell-mediated ECM deposition in vitro. In the current study, we hypothesized that HA can act as a MMC, and increase cell-mediated ECM production. Human dermal fibroblasts were cultured for 3, 7, or 14 days with 0%, 0.05%, or 0.5% high molecular weight HA. Ficoll 70/400 was used as a positive control. SDS-PAGE, Sircol, and hydroxyproline assays indicated that 0.05% HA-treated cultures had significantly higher mean collagen deposition at 14 days, whereas Ficoll 70/400-treated cultures had significantly lower collagen production compared to the HA and untreated controls. However, fluorescent immunostaining of ECM proteins and quantification of mean gray values did not indicate statistically significant differences in ECM production in HA or Ficoll 70/400-treated cultures compared to untreated controls. Raman imaging (a marker-free spectral imaging method) indicated that HA increased ECM deposition in human dermal fibroblasts. These results are consistent with decreases in CDM stiffness observed in Ficoll 70/400-treated cultures by atomic force microscopy. Overall, these results indicate that there are macromolecule- and cell type- dependent effects on matrix assembly, turnover, and stiffness in cell-derived matrices. STATEMENT OF SIGNIFICANCE: Cell-derived matrices (CDMs) are versatile biomaterials with many regenerative medicine applications, including as cell and drug delivery vehicles and scaffolds for wound healing and tissue regeneration. While CDMs have several advantages, their commercialization has been limited due to the prolonged culture time required to achieve CDM synthesis in vitro. In this study, we explored the use of hyaluronic acid (HA) as a macromolecular crowder in human fibroblast cell cultures to support production of CDM biomaterials. Successful application of macromolecular crowding will allow development of human cell-derived, xeno-free biomaterials that re-capitulate the native human tissue microenvironment., (Copyright © 2019 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Smooth muscle cells (SMCs) are essential for tissue engineering strategies to fabricate organs such as blood vessels, the oesophagus and bladder, and to create disease models of these systems. In order for such therapies and models to be feasible, SMCs must be sourced effectively to enable production of large numbers of functional cells. In vitro, SMCs divide slowly and demonstrate short proliferative lifespans compared with other types of cells, including stem cells and fibroblasts, limiting the number of cells that can be derived from expansion in culture of a primary isolation. As such, it would be beneficial to better understand the factors underlying induction and maintenance of SMC phenotypes, in order to produce new sources of SMCs for tissue engineering and disease modelling. Here we report the ability of human dermal fibroblasts to display patterns of gene expression resembling contractile SMCs when cultured under conditions that are known to promote a contractile phenotype in SMCs, including culture on collagen IV, low-serum culture, TGF-β1 treatment and hypoxia. These factors drive expression of the myogenic transcription factor myocardin, as well as expression of several of its gene targets that are known contributors to contractile phenotype in SMCs, including smooth muscle alpha actin, calponin, and myosin heavy chain. Our results suggest that culture conditions associated with culture of SMCs may be sufficient to induce myogenic gene expression patterns and potential myogenic function in non-muscle cells., (Copyright © 2017 John Wiley & Sons, Ltd.)

Basic fibroblast growth factor (FGF2) is a highly pleiotropic member of a large family of growth factors with a broad range of activities, including mitogenesis and angiogenesis (Ornitz et al., 1996; Zhang et al., 2006), and it is known to be essential for maintenance of balance between survival, proliferation, and self-renewal in human pluripotent stem cells (Eiselleova et al., 2009; Zoumaro-Djayoon et al., 2011). A single FGF2 transcript can be translated into five FGF2 protein isoforms, an 18kDa low molecular weight (LMW) isoform and four larger high molecular weight (HMW) isoforms (Arese et al., 1999; Arnaud et al., 1999). As they are not generally secreted, high molecular weight (HMW) FGF2 isoforms have predominantly been investigated intracellularly; only a very limited number of studies have investigated their activity as extracellular factors. Here we report over-expression, isolation, and biological activity of all recombinant human FGF2 isoforms. We show that HMW FGF2 isoforms can support self-renewal of human embryonic stem cells (hESCs) in vitro. Exogenous supplementation with HMW FGF2 isoforms also activates the canonical FGFR/MAPK pathway and induces mitogenic activity in a manner similar to that of the 18kDa FGF2 isoform. Though all HMW isoforms, when supplemented exogenously, are able to recapitulate LMW FGF2 activity to some degree, it appears that certain isoforms tend to do so more poorly, demonstrating a lesser functional response by several measures. A better understanding of isoform-specific FGF2 effects will lead to a better understanding of developmental and pathological FGF2 signaling., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

The study of cellular senescence and proliferative lifespan is becoming increasingly important because of the promises of autologous cell therapy, the need for model systems for tissue disease and the implication of senescent cell phenotypes in organismal disease states such as sarcopenia, diabetes and various cancers, among others. Here, we explain the concepts of proliferative cellular lifespan and cellular senescence, and we present factors that have been shown to mediate cellular lifespan positively or negatively. We review much recent literature and present potential molecular mechanisms by which lifespan mediation occurs, drawing from the fields of telomere biology, metabolism, NAD(+) and sirtuin biology, growth factor signaling and oxygen and antioxidants. We conclude that cellular lifespan and senescence are complex concepts that are governed by multiple independent and interdependent pathways, and that greater understanding of these pathways, their interactions and their convergence upon specific cellular phenotypes may lead to viable therapies for tissue regeneration and treatment of age-related pathologies, which are caused by or exacerbated by senescent cells in vivo., (© 2016 The Authors. BioEssays published by WILEY Periodicals, Inc.)