Development of "Explore Plastic Surgery": An Educational Program for Medical Students Without Home Residency Programs.

BACKGROUND: Medical students who attend institutions without plastic surgery residency programs are at a disadvantage in the plastic surgery match. We developed an educational program for medical students without home programs called Explore Plastic Surgery to provide an overview of the steps toward a career in plastic surgery. The purpose of this study was to assess the impact, utility, and success of the novel program. METHODS: Pre- and postevent surveys were distributed to participants. Survey data were analyzed including participant demographics, perceptions of barriers unique to those without home programs, and the overall event utility. RESULTS: Two hundred seventeen students registered for the program. Ninety-five participants completed the pre-event survey (44%), and of those, 57 participants completed the post-event survey (60%). There was an increase in understanding of the steps toward a career in plastic surgery ( P < 0.001), confidence in overcoming barriers ( P = 0.005), and level of comfort in reaching out to faculty for opportunities ( P = 0.01). There was a decrease in the perceived negative impact that attending medical schools without a home program will have on their abilities to pursue careers in plastic surgery ( P = 0.006). CONCLUSIONS: After the event, participants demonstrated an increase in their confidence in overcoming barriers and a decrease in their perceptions that attending an institution without a home program would negatively impact their ability to pursue plastic surgery. Initiatives focused on early exposure and recruitment of medical students may be important to promote accessibility and diversity within plastic surgery.

Fat grafting rescues radiation-induced joint contracture.

The aim of this study was to explore the therapeutic effects of fat grafting on radiation-induced hind limb contracture. Radiation therapy (RT) is used to palliate and/or cure a range of malignancies but causes inevitable and progressive fibrosis of surrounding soft tissue. Pathological fibrosis may lead to painful contractures which limit movement and negatively impact quality of life. Fat grafting is able to reduce and/or reverse radiation-induced soft tissue fibrosis. We explored whether fat grafting could improve extensibility in irradiated and contracted hind limbs of mice. Right hind limbs of female 60-day-old CD-1 nude mice were irradiated. Chronic skin fibrosis and limb contracture developed. After 4 weeks, irradiated hind limbs were then injected with (a) fat enriched with stromal vascular cells (SVCs), (b) fat only, (c) saline, or (d) nothing (n = 10/group). Limb extension was measured at baseline and every 2 weeks for 12 weeks. Hind limb skin then underwent histological analysis and biomechanical strength testing. Irradiation significantly reduced limb extension but was progressively rescued by fat grafting. Fat grafting also reduced skin stiffness and reversed the radiation-induced histological changes in the skin. The greatest benefits were found in mice injected with fat enriched with SVCs. Hind limb radiation induces contracture in our mouse model which can be improved with fat grafting. Enriching fat with SVCs enhances these beneficial effects. These results underscore an attractive approach to address challenging soft tissue fibrosis in patients following RT.

Longitudinal study of breast cancer risk markers.

Atypical hyperplasia (AH) and lobular carcinoma in situ (LCIS) are markers for an increased risk of breast cancer, yet outcomes for these diagnoses are not well-documented. In this study, all breast biopsies performed for radiologic abnormalities over a 10-year period were reviewed. Patients with AH or LCIS were followed for an additional 10 years to assess subsequent rates of cancer diagnosis. Long-term follow-up showed that 25 (7.8%) patients with AH and 5 patients with LCIS (5.7%) developed breast cancer over the follow-up period, a lower rate of breast cancer development than predicted by risk models.

Reflecting on the Human Connection.

A medical student describes a relationship with a cancer patient, the privilege of human connections in life, and the lessons learned from a first experience with death.

Prognostic Significance of Residual Axillary Nodal Micrometastases and Isolated Tumor Cells After Neoadjuvant Chemotherapy for Breast Cancer.

BACKGROUND: The prognostic significance of low-volume residual nodal disease following neoadjuvant chemotherapy (NAC) is unknown. METHODS: Women with cT1-4N0-1 breast cancer treated with NAC were identified from Dana-Farber/Brigham and Women's Cancer Center (DFBWCC) and the National Cancer Database (NCDB). Disease-free survival (DFS) and overall survival (OS) estimates according to pathologic nodal status were calculated using the Kaplan-Meier method, with Cox proportional hazards regression used to assess the effect of clinical variables on survival outcomes. RESULTS: Among 967 DFBWCC patients, 27 (2.8%) had residual isolated tumor cells (ITCs) and 61 (6.3%) had micrometastases. Five-year DFS was significantly worse in those with residual ITCs (73.5%) and micrometastases (74.7%) relative to those who were ypN0 following NAC (88.4%, p < 0.001). On adjusted analysis, those with residual ITCs (hazard ratio [HR] 2.4, 95% confidence interval [CI] 1.20-3.81) and micrometastases (HR 2.14, 95% CI 1.20-3.81) had increased risk of recurrence relative to ypN0 patients. Among 35,536 NCDB patients, 543 (1.5%) had ITCs and 1132 (3.2%) had micrometastases. Five-year OS estimates were significantly worse with increasing residual nodal burden: ypN0, 88.9%; ypN0[i+], 82.8%; ypN1mi, 79.5%; ypN1, 77.6% (p < 0.001). Compared with patients with ypN0 disease, NCDB patients with ITCs and micrometastases had 1.9- and 2.2-fold risk of death (p < 0.001). On subgroup analysis, the effect of low-volume residual disease on mortality was most pronounced in patients with triple-negative and human epidermal growth factor receptor 2 (HER2)-positive disease. CONCLUSIONS: Low-volume residual nodal disease following NAC is associated with poorer DFS and OS relative to those who are node negative.

Adherence to oral chemotherapy: Challenges and opportunities.

PURPOSE: There is very little data on the effect of combining methods to better predict and improve oral antineoplastic adherence in cancer patients. The goal of this study was to evaluate the effectiveness of an intensive pharmacist intervention at the beginning of oral antineoplastic therapy versus nurse-led control group on adherence. METHODS: This was a prospective, randomized, open-label controlled trial performed in a single center hematology/oncology outpatient service to compare the effectiveness of repetitive pharmacist educational intervention on adherence rates measured at four and eight weeks after prescribing oral antineoplastic medication compared to a nurse-led control group. Both groups included investigator pill counts and self-report adherence questionnaires. RESULTS: Two-hundred patients were enrolled between 2009 and 2015. Fourteen of the 101 (14%) patients in the pharmacist group and 7 (7%) of the 99 patients in the nurse-led control group dropped out (p = 0.166). The majority of patients who remained in the study were 90-100% adherent to oral antineoplastic therapy in both groups. The pharmacist group slightly underperformed at Pill Count 2, possibly due to barriers for non-adherence. Statistically significant correlations associated with non-adherence were forgetfulness (p = 0.009), wanting to avoid side effects (p = 0.02), feeling depressed or overwhelmed (p = 0.032), or falling asleep before taking medication (p = 0.048) in both groups. CONCLUSION: The combination of pill count and patient self-report adherence is a way of improving oral antineoplastic adherence. However, significant barriers to adherence were identified such as forgetfulness, wanting to avoid side effects, feeling depressed or overwhelmed, and falling asleep before taking medications.

Radiation-Induced Skin Fibrosis: Pathogenesis, Current Treatment Options, and Emerging Therapeutics.

Radiotherapy (RT) has become an indispensable part of oncologic treatment protocols for a range of malignancies. However, a serious adverse effect of RT is radiodermatitis; almost 95% of patients develop moderate to severe skin reactions following radiation treatment. In the acute setting, these can be erythema, desquamation, ulceration, and pain. Chronically, soft tissue atrophy, alopecia, and stiffness can be noted. Radiodermatitis can delay oncologic treatment protocols and significantly impair quality of life. There is currently a paucity of effective treatment options and prevention strategies for radiodermatitis. Importantly, recent preclinical and clinical studies have suggested that fat grafting may be of therapeutic benefit, reversing detrimental changes to soft tissue following RT. This review outlines the damaging effects of RT on the skin and soft tissue as well as discusses available treatment options for radiodermatitis. Emerging strategies to mitigate detrimental, chronic radiation-induced changes are also presented.

Complex Regional Pain Syndrome, Current Concepts and Treatment Options.

PURPOSE OF REVIEW: Complex regional pain syndrome (CRPS) refers to a chronic pain condition that is characterized by progressively worsening spontaneous regional pain without dermatomal distribution. The symptomatology includes pain out of proportion in time and severity to the inciting event. The purpose of this review is to present the most current information concerning epidemiology, diagnosis, pathophysiology, and therapy for CRPS. RECENT FINDINGS: In recent years, discovery of pathophysiologic mechanisms of CRPS has led to significant strides in the understanding of the disease process. Continued elucidation of the underlying pathophysiological mechanisms will allow for the development of more targeted and effective evidence-based therapy protocols. Further large clinical trials are needed to investigate mechanisms and treatment of the disorder.

Early remodeling of the neocortex upon episodic memory encoding.

Understanding the mechanisms by which long-term memories are formed and stored in the brain represents a central aim of neuroscience. Prevailing theory suggests that long-term memory encoding involves early plasticity within hippocampal circuits, whereas reorganization of the neocortex is thought to occur weeks to months later to subserve remote memory storage. Here we report that long-term memory encoding can elicit early transcriptional, structural, and functional remodeling of the neocortex. Parallel studies using genome-wide RNA sequencing, ultrastructural imaging, and whole-cell recording in wild-type mice suggest that contextual fear conditioning initiates a transcriptional program in the medial prefrontal cortex (mPFC) that is accompanied by rapid expansion of the synaptic active zone and postsynaptic density, enhanced dendritic spine plasticity, and increased synaptic efficacy. To address the real-time contribution of the mPFC to long-term memory encoding, we performed temporally precise optogenetic inhibition of excitatory mPFC neurons during contextual fear conditioning. Using this approach, we found that real-time inhibition of the mPFC inhibited activation of the entorhinal-hippocampal circuit and impaired the formation of long-term associative memory. These findings suggest that encoding of long-term episodic memory is associated with early remodeling of neocortical circuits, identify the prefrontal cortex as a critical regulator of encoding-induced hippocampal activation and long-term memory formation, and have important implications for understanding memory processing in healthy and diseased brain states.

Plastic Surgery Residency Applicants' Perceptions of a Virtual Interview Cycle.

BACKGROUND: The 2020 to 2021 residency application cycle marked the first year of fully virtual integrated plastic surgery interviews. The virtual format was a double-edged sword for applicants with several advantages, such as reduced costs and time lost from travel, and disadvantages as the novel format introduced new stressors on top of an already demanding process. Concerns included unfair interview invitation distribution, interview "hoarding," and assessing "fit" virtually. In this study, the authors aimed to understand applicants' experiences of the 2020 to 2021 virtual plastic surgery interview cycle. METHODS: A survey was sent to 330 applicants in the 2020 to 2021 integrated plastic surgery application cycle. The survey included questions about participant demographics, preinterview preparation, virtual interview experiences, and postinterview process. Statistical comparisons were performed on responses using IBM SPSS Statistics version 25.0 (IBM, Armonk, N.Y.). RESULTS: Eighty-nine participants responded to the survey, representing a 27 percent response rate. Applicants received an average of 13.3 interview invitations (range, 0 to 45) and attended an average of 11.4 interviews (range, 0 to 30). Almost half (48.2 percent) did not feel interview invitations were distributed equitably, and more than half (68.2 percent) reported that there should be a limit on the number of interview invitations an applicant can accept. The majority of respondents (88.1 percent) reported spending $500 or less on virtual interviews. Half (50.6 percent) participated in virtual subinternships, of which 30.4 percent became significantly less interested in a program afterward. CONCLUSIONS: The inaugural virtual interview cycle had several advantages and disadvantages. Lessons learned from this year could be utilized toward building a more equitable, fair, and effective potential virtual cycle in years to come.

Designing a Plastic and Reconstructive Surgery Virtual Curriculum: Assessment of Medical Student Knowledge, Surgical Skill, and Community Building.

BACKGROUND: The COVID-19 pandemic displaced medical students from their rotations and into virtual classrooms. The authors aimed to develop a virtual curriculum with the goals for students to gain knowledge in plastic surgery, to acquire technical skills, and to be able to promote community. METHODS: The authors developed a 4-week educational curriculum of topics in plastic surgery using the American Society of Plastic Surgeons Resident Education Curriculum and an online plastic surgery curriculum. Virtual flipped classroom case discussions and weekly surgical skills workshops were offered. Precourse and postcourse surveys were administered, and results were analyzed using IBM SPSS Statistics version 25.0. RESULTS: Three hundred three medical students and recent graduates enrolled in the course in June of 2020. One hundred eighty-two students completed the precourse survey (60 percent response rate), and of those, 50.0 percent ( n = 91) completed the postcourse survey for paired comparison. Students reported significant improvement in confidence discussing the relevant anatomy, workup, and surgical approaches to clinical cases, in addition to confidence in knowledge of all topic areas ( p < 0.001). Confidence in suturing and knot-tying techniques improved significantly among workshop participants ( p < 0.001). Students applying to residency programs this cycle felt significantly more prepared for subinternships ( p < 0.001) and significantly more connected to the community of applicants ( p < 0.001). CONCLUSIONS: The Plastic and Reconstructive Surgery Virtual Curriculum improved knowledge, surgical skills, and community in the field among medical student participants. This course may serve to provide a framework for structured virtual learning activities for students interested in plastic surgery and may have significant long-lasting utility for students interested in the field.

If You Can See It, You Can Be It: Perceptions of Diversity in Surgery Among Under-Represented Minority High School Students.

PURPOSE: Increasing racial and ethnic diversity in the surgical workforce is essential to improving outcomes for marginalized communities. To address the persistent shortage of under-represented minority (URM) surgeons, this study assessed the impact of providing early exposure to the field of surgery on URM high school students' perceptions of pursuing surgical careers. METHODS: The Association of Women Surgeons organized a pilot 3-hour "Day in the Life" virtual event geared toward URM high school students involving suturing/knot-tying, case conferences, and mentoring activities. RESULTS: Pre- and post-event survey results from 65 participants showed that students became more familiar with surgery (p < 0.001) and perceived the field as more diverse (p = 0.017). Over 70% felt capable of becoming surgeons themselves and over 80% were interested in learning more and gaining mentorship. CONCLUSIONS: Our programming provides a model for future initiatives aimed at strengthening the pipeline of URM surgeons.

Profibrotic Signaling Pathways and Surface Markers Are Up-Regulated in Fibroblasts of Human Striae Distensae and in a Mouse Model System.

BACKGROUND: Striae distensae are common disfiguring cutaneous lesions but lack effective treatments because of an incomplete understanding of their pathophysiology. Dermal fibroblasts likely play an important role. The authors investigate the cellular-molecular features distinguishing fibroblasts from human striae distensae and normal skin. The authors also develop a mouse model of striae distensae. METHODS: Human striae distensae and normal skin samples were compared for tensile strength and histologic structure. Fibroblasts from striae distensae and normal skin were isolated by fluorescence-activated cell sorting for gene expression analysis. Immunofluorescence staining and fluorescence-activated cell sorting were used to confirm gene expression data at the protein level. A mouse model of striae distensae formation was created by administering corticosteroids and mechanically loading the dorsal skin. RESULTS: Human striae distensae exhibited reduced tensile strength, more disordered collagen fibers, and epidermal atrophy compared to human normal skin. There were 296 up-regulated genes in striae distensae fibroblasts, including the profibrotic lineage and surface marker CD26. Up-regulated genes were involved in profibrotic and mechanoresponsive signaling pathways (TGFß and FAK-PI3-AKT-signaling). In contrast, 571 genes were down-regulated, including CD74 and genes of the AMPK pathway. Increased CD26 and decreased CD74 expression was confirmed by fluorescence-activated cell sorting and immunofluorescence. Similar cutaneous histologic and gene expression changes were induced in hypercortisolemic mice by mechanically loading the dorsal skin. CONCLUSIONS: Fibroblasts from human striae distensae exhibit increased profibrotic and decreased antifibrotic signaling. CD26 and CD74 are promising surface markers that may be targeted therapeutically. The authors' mouse model of striae distensae can be used as a platform to test the efficacy of potential therapeutic agents. CLINICAL RELEVANCE STATEMENT: Striae distensae are common disfiguring cutaneous lesions whose etiology remains elusive, which has hindered development of effective treatment strategies. Dermal fibroblasts likely play an important role. The authors sought to elucidate the key cellular-molecular pathways distinguishing fibroblasts in striae distensae from those in normal skin.

A Novel Xenograft Model Demonstrates Human Fibroblast Behavior During Skin Wound Repair and Fibrosis.

Objective: Xenografts of human skin in immunodeficient mice provide a means of assessing human skin physiology and its response to wounding. Approach: We describe a novel xenograft model using full-thickness human neonatal foreskin to examine human skin wound repair. Full-thickness 8 mm human neonatal foreskin biopsies were sutured into the dorsum of NOD scid gamma (NSG; NOD.Cg-Prkdc scidIl2rgtm1Wjl/SzJ) pups as subcutaneous grafts. At postnatal day 21 the subcutaneous grafts were exposed to cutaneous grafts. Following maturation of 2 months, xenografts were then wounded with 5 mm linear incisions and monitored until postwound day (PWD) 14 to study skin repair and fibrosis. To explore whether our model can be used to test the efficacy of topical therapies, wounded xenografts were injected with antifibrotic fibroblast growth factor 2 (FGF2) for the first four consecutive PWDs. Xenografts were harvested for analysis by histology and fluorescence-activated cell sorting (FACS). Results: Xenografts were successfully engrafted with evidence of mouse-human anastomoses and resembled native neonatal foreskin at the gross and microscopic level. Wounded xenografted skin scarred with human collagen and an expansion of CD26-positive human fibroblasts. Collagen scar was quantitated by neural network analysis, which revealed distinct clustering of collagen fiber networks from unwounded skin and wounded skin at PWD7 and PWD14. Collagen fiber networks within FGF2-treated wounds at PWD14 resembled those in untreated wounded xenografts at PWD7, suggesting that FGF2 treatment at time of wounding can reduce fibrosis. Innovation and Conclusion: This novel xenograft model can be used to investigate acute fibrosis, fibroblast heterogeneity, and the efficacy of antifibrotic agents during wound repair in human skin.

Decellularized Adipose Matrices Can Alleviate Radiation-Induced Skin Fibrosis.

Objective: Radiation therapy is commonplace for cancer treatment but often results in fibrosis and atrophy of surrounding soft tissue. Decellularized adipose matrices (DAMs) have been reported to improve these soft tissue defects through the promotion of adipogenesis. These matrices are decellularized by a combination of physical, chemical, and enzymatic methods to minimize their immunologic effects while promoting their regenerative effects. In this study, we aimed at exploring the regenerative ability of a DAM (renuva®; MTF biologics, Edison, NJ) in radiation-induced soft tissue injury. Approach: Fresh human lipoaspirate or DAM was injected into the irradiated scalp of CD-1 nude mice, and volume retention was monitored radiographically over 8 weeks. Explanted grafts were histologically assessed, and overlying skin was examined histologically and biomechanically. Irradiated human skin was also evaluated from patients after fat grafting or DAM injection. However, integrating data between murine and human skin in all cohorts is limited given the genetic variability between the two species. Results: Volume retention was found to be greater with fat grafts, though DAM retention was, nonetheless, appreciated at irradiated sites. Improvement in both mouse and human irradiated skin overlying fat and DAM grafts was observed in terms of biomechanical stiffness, dermal thickness, collagen density, collagen fiber networks, and skin vascularity. Innovation: This is the first demonstration of the use of DAMs for augmenting the regenerative potential of irradiated mouse and human skin. Conclusions: These findings support the use of DAMs to address soft tissue atrophy after radiation therapy. Morphological characteristics of the irradiated skin can also be improved with DAM grafting.

Evaluation of Social Media Utilization by Academic Plastic Surgery Programs during the COVID-19 Pandemic.

BACKGROUND: In response to the cancellation of away rotations and the shift to virtual interviews due to the coronavirus disease of 2019 (COVID-19) pandemic, residency programs have pursued other methods of sharing program details, most notably with the use of social media. This study aimed to evaluate the extent of social media utilization in the setting of the COVID-19 pandemic by plastic surgery residency programs. METHODS: Instagram, Twitter, and Facebook accounts of plastic surgery programs, program directors, and chiefs were identified. Number of followers, total posts, and posts since March 1, 2020, were extracted. Account content was categorized as informational, social, operative, research, self-promotional, guest lecture, education, or other. Spearman's coefficient was used to determine correlations among account data. Differences among regions and program pathways were evaluated using the Kruskal-Wallis test. RESULTS: Since March 1, 2020, 17 Instagram, five Twitter, and three Facebook accounts have been created. Instagram was most widely used and followed (1720 posts, 1235.7 ± 735.9 followers) compared with Twitter (722 tweets, 325.6 ± 451.0 followers) and Facebook (430 posts, 338.3 ± 363.3 followers). Although the majority of content was informational (45.1 percent), Instagram contained more social content (21 percent), Twitter contained more research (21 percent), and Facebook contained more self-promotional content (25 percent). Integrated-only programs on average posted more on Instagram (21.5 ± 15.1 posts) than did independent-only programs (9.4 ± 8.5 posts), and post volume moderately correlated with number of followers. There were no statistically significant differences among regional means. CONCLUSION: Plastic surgery residency programs have incorporated social media into their recruitment strategies and will likely continue to increase and diversify their posts to effectively engage with future applicants.

Virtual Interviews for the Integrated Plastic Surgery Residency Match: The Program Director Perspective.

Interviews for the integrated plastic surgery residency match took place in a virtual format for the 2020-2021 application cycle. Current literature lacks the perspectives of program directors (PDs) on virtual interviews compared with traditional in-person interviews. METHODS: Following institutional review board approval, an anonymous 17-question survey was distributed by email to 82 program directors of integrated plastic surgery residency programs in the United States. Participants were asked baseline program information, the number of positions and interview invites offered, and their perspectives on various aspects of the virtual interview process. RESULTS: Sixty-two (75.6%) PDs completed the survey. Thirty-seven percent reported increasing the number of interview offers per available residency spot. On a five-point Likert scale (1, not well at all; 5, extremely well), PDs showed no significant differences in their ability judge an applicant's professionalism (3.1 ± 1.1), interpersonal and communication skills (3.2 ± 1.1), and "fit" with their program (2.9 ± 0.9) during virtual interviews (P = 0.360). Sixty-eight percent reported being satisfied (15.3% extremely satisfied, 52.5% somewhat satisfied) with the virtual interview process, though 76.3% preferred in-person interviews. CONCLUSIONS: This study is the first to provide insight into PDs' impressions of virtual residency interviews. Although most reported being satisfied with the virtual interview process, the majority still preferred in-person interviews. Further long-term studies evaluating the pros and cons of each interview modality may provide more information on whether virtual interviews could become a sustainable alternative to the traditional in-person residency interview.

Angiogenic CD34+CD146+ adipose-derived stromal cells augment recovery of soft tissue after radiotherapy.

Radiation therapy is effective for cancer treatment but may also result in collateral soft tissue contracture, contour deformities, and non-healing wounds. Autologous fat transfer has been described to improve tissue architecture and function of radiation-induced fibrosis and these effects may be augmented by enrichment with specific adipose-derived stromal cells (ASCs) with enhanced angiogenic potential. CD34+CD146+, CD34+CD146-, or CD34+ unfractionated human ASCs were isolated by flow cytometry and used to supplement human lipoaspirate placed beneath the scalp of irradiated mice. Volume retention was followed radiographically and fat grafts as well as overlying soft tissue were harvested after eight weeks for histologic and biomechanical analyses. Radiographic evaluation revealed the highest volume retention in fat grafts supplemented with CD34+CD146+ ASCs, and these grafts were also found to have greater histologic integrity than other groups. Irradiated skin overlying CD34+CD146+ ASC-enriched grafts was significantly more vascularized than other treatment groups, had significantly less dermal thickness and collagen deposition, and the greatest improvement in fibrillin staining and return of elasticity. Radiation therapy obliterates vascularity and contributes to scarring and loss of tissue function. ASC-enrichment of fat grafts with CD34+CD146+ ASCs not only enhances fat graft vascularization and retention, but also significantly promotes improvement in overlying radiation-injured soft tissue. This regenerative effect on skin is highly promising for patients with impaired wound healing and deformities following radiotherapy.

Preventing Engrailed-1 activation in fibroblasts yields wound regeneration without scarring.

Skin scarring, the end result of adult wound healing, is detrimental to tissue form and function. Engrailed-1 lineage-positive fibroblasts (EPFs) are known to function in scarring, but Engrailed-1 lineage-negative fibroblasts (ENFs) remain poorly characterized. Using cell transplantation and transgenic mouse models, we identified a dermal ENF subpopulation that gives rise to postnatally derived EPFs by activating Engrailed-1 expression during adult wound healing. By studying ENF responses to substrate mechanics, we found that mechanical tension drives Engrailed-1 activation via canonical mechanotransduction signaling. Finally, we showed that blocking mechanotransduction signaling with either verteporfin, an inhibitor of Yes-associated protein (YAP), or fibroblast-specific transgenic YAP knockout prevents Engrailed-1 activation and promotes wound regeneration by ENFs, with recovery of skin appendages, ultrastructure, and mechanical strength. This finding suggests that there are two possible outcomes to postnatal wound healing: a fibrotic response (EPF-mediated) and a regenerative response (ENF-mediated).

JUN promotes hypertrophic skin scarring via CD36 in preclinical in vitro and in vivo models.

Pathologic skin scarring presents a vast economic and medical burden. Unfortunately, the molecular mechanisms underlying scar formation remain to be elucidated. We used a hypertrophic scarring (HTS) mouse model in which Jun is overexpressed globally or specifically in α-smooth muscle or collagen type I­expressing cells to cause excessive extracellular matrix deposition by skin fibroblasts in the skin after wounding. Jun overexpression triggered dermal fibrosis by modulating distinct fibroblast subpopulations within the wound, enhancing reticular fibroblast numbers, and decreasing lipofibroblasts. Analysis of human scars further revealed that JUN is highly expressed across the wide spectrum of scars, including HTS and keloids. CRISPR-Cas9­mediated JUN deletion in human HTS fibroblasts combined with epigenomic and transcriptomic analysis of both human and mouse HTS fibroblasts revealed that JUN initiates fibrosis by regulating CD36. Blocking CD36 with salvianolic acid B or CD36 knockout model counteracted JUN-mediated fibrosis efficacy in both human fibroblasts and mouse wounds. In summary, JUN is a critical regulator of pathological skin scarring, and targeting its downstream effector CD36 may represent a therapeutic strategy against scarring.