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Background: Autologous and allogeneic platelet-rich plasma (PRP) in addition to its derivatives, such as platelet-rich fibrin (PRF), are broadly accepted therapeutic approaches in orthopedics, otolaryngology, sports medicine, plastic surgery, and oral and maxillofacial surgery. However, the absence of expert consensus, standardized protocols, and varying outcomes pose challenges to their broader acceptance in cosmetic dermatology and dermatologic surgery., Objective: To offer a contemporary literature overview of PRP and PRF, focusing on fundamental aspects of the technology, diversity of commercially accessible systems, and shed light on present-day controversies within the field., Methods: A systemic review of PRP and PRF literature was conducted, utilizing search engine databases: Cochrane Database of Systematic Reviews, Embase, Ovid MEDLINE, and PubMed. Emphasis was placed on scrutinizing higher level-of-evidence articles, specifically randomized control trials, systematic reviews, and meta-analyses (Level 1A-2A), with particular emphasis on recent data that have not been well reviewed in other publications from January 2022 to May 2024., Results: An increasing body of literature affirms advantages of PRP products in dermatology, spanning wound care, facial rejuvenation, scar revision, and hair growth., Conclusion: A foundational understanding of variation in preparation protocol, outcomes, and timing of administration is needed to better comprehend market dynamics, patient demand, and strategies for integrating PRP into dermatologic practice., (Copyright © 2024 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Background: Cellular senescence, an irreversible cell cycle arrest with secretory phenotype, is a hallmark of skin aging. Regenerative exosome-based approaches, such as topical human platelet extract (HPE), are emerging to target age-related skin dysfunction., Objective: To evaluate the cellular and molecular effects of topical HPE for skin rejuvenation after 12 weeks of twice daily use., Methods: Skin biopsies were obtained for histological evaluation of senescence markers, p16INK4a and p21CIP1/WAF1. Telomere-associated foci, coassociation of telomeres, and DNA damage marker, γH2AX, were assessed. RNA sequencing evaluated senescence associated secretory phenotype (SASP) and extracellular matrix pathways., Results: p16INK4a and p21CIP1/WAF1 staining in senescent skin cells revealed low and high expression subgroups that did not correspond to chronological age. Topical HPE significantly reduced high p16INK4a cells in the dermis (p = .02). There was also a decrease in telomere damage after topical HPE (p = .03). In patients with high senescent cells at baseline, there was a 40% reduction in proinflammatory SASP. Extracellular matrix remodeling pathways, including collagen and elastic fibers, were up-regulated., Conclusion: Topical HPE, applied on intact skin, reduced senescence signaling and senescence-associated telomere damage after 12 weeks of twice daily use, targeting a path for skin longevity or healthy skin aging., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Society for Dermatologic Surgery, Inc.)

Cellular senescence is an established cause of cell and tissue aging. Senescent cells have been shown to increase in multiple organs during aging, including the skin. Here we hypothesized that senescent cells residing in the skin can spread senescence to distant organs, thereby accelerating systemic aging processes. To explore this hypothesis, we initially observed an increase in several markers of senescence in the skin of aging mice. Subsequently, we conducted experiments wherein senescent fibroblasts were transplanted into the dermis of young mice and assessed various age-associated parameters. Our findings reveal that the presence of senescent cells in the dermal layer of young mice leads to increased senescence in both proximal and distal host tissues, alongside increased frailty, and impaired musculoskeletal function. Additionally, there was a significant decline in cognitive function, concomitant with increased expression of senescence-associated markers within the hippocampus brain area. These results support the concept that the accumulation of senescent cells in the skin can exert remote effects on other organs including the brain, potentially explaining links between skin and brain disorders and diseases and, contributing to physical and cognitive decline associated with aging., (© 2024 The Author(s). Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Single-cell RNA sequencing and spatial transcriptomics enable unprecedented insight into cellular and molecular pathways implicated in human skin aging and regeneration. Senescent cells are individual cells that are irreversibly cell cycle arrested and can accumulate across the human lifespan due to cell-intrinsic and -extrinsic stressors. With an atlas of single-cell RNA-sequencing and spatial transcriptomics, epidermal and dermal senescence and its effects were investigated, with a focus on melanocytes and fibroblasts. Photoaging due to ultraviolet light exposure was associated with higher burdens of senescent cells, a sign of biological aging, compared to chronological aging. A skin-specific cellular senescence gene set, termed SenSkin™, was curated and confirmed to be elevated in the context of photoaging, chronological aging, and non-replicating CDKN1A+ (p21) cells. In the epidermis, senescent melanocytes were associated with elevated melanin synthesis, suggesting haphazard pigmentation, while in the dermis, senescent reticular dermal fibroblasts were associated with decreased collagen and elastic fiber synthesis. Spatial analysis revealed the tendency for senescent cells to cluster, particularly in photoaged skin. This work proposes a strategy for characterizing age-related skin dysfunction through the lens of cellular senescence and suggests a role for senescent epidermal cells (i.e., melanocytes) and senescent dermal cells (i.e., reticular dermal fibroblasts) in age-related skin sequelae., (© 2024 The Author(s). Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Summary: Aging of the face is the result of the interrelation of three-dimensional changes occurring over time among the 5 different layers of the face and its associated structures. Knowledge regarding the causes of these changes and identification of new key anatomic structures have helped elucidate one of the most complex areas of the human body. This has resulted in the introduction of pharmacologic agents to help stop, mitigate, or counteract signs of aging and restore the youthful appearance of the face. The authors performed a systematic search of the literature to review the current highest-level evidence of facial antiaging pharmacologic agents. Pharmacologic and minimally invasive antiaging treatments can target different components of facial aging and continue to evolve. With continuous research efforts, traditional treatments, such as botulinum toxin type A, injectable fillers, and chemical peels, are emerging in newer, more effective formulations, with longer lasting clinical results. However, for soft-tissue descent and facial volume loss, surgery remains the standard treatment. An adequate understanding of the three-dimensional process of facial aging over time (the fourth dimension), facial anatomy, and the pharmacologic properties of antiaging/rejuvenation agents are the sine qua non of facial antiaging treatment. The specific modality should be tailored to patient characteristics, preferences, and goals., (Copyright © 2023 by the American Society of Plastic Surgeons.)

Two monozygotic twins (Fitzpatrick skin type II 56-year-old women) with significant photoaging and mild to moderate global fine lines based on the modified Griffiths 10-point scale were enrolled in the study. The past medical etymology and laboratory evaluation were unremarkable. Each subject followed a standardized skin care regimen with topical platelet renewosomes TM (human platelet extract [HPE]) daily for a 12-week duration. 1-4 In order to evaluate aesthetic outcomes/changes subjectively, three blinded board-certified plastic surgeons (Yael Halaas, K. Kay Durairaj, and Michael Somenek) compared photographs between baseline and 12-week follow-up (Figure 1). This evaluation was completed using the Global Aesthetic Improvement Scale (GAIS) and the modified Griffiths 10-point scale. 5,6 .

Background: Regenerative aesthetics has garnered significant attention. In this toolkit, exosomes are small extracellular vesicles derived from various sources such as platelets., Objective: To characterize the cosmetic effect and tolerability of topical human platelet-derived extract (HPE), Intense Serum (Rion Aesthetics, Inc., Rochester, MN), on facial skin rejuvenation after 12 weeks of twice daily use without any confounding aesthetic procedures., Materials and Methods: This prospective, single-arm, non-randomized, evaluator-blinded clinical study evaluated subjects at baseline and 12 weeks using participant questionnaires and photo-documentation with Canfield VISIA-CR 3D PRIMOS. The histological evaluation included Masson's Trichrome for collagen and Verhoeff-Van Gieson staining for elastin. Electron microscopy characterized collagen bundle thickness., Results: Fifty-six participants (mean age: 54 years old) were enrolled. Following topical HPE use, 87.3% of subjects reported improvement in facial skin aging including sustained pigment reduction and improvement in luminosity and color evenness at 12 weeks (P≤0.001). Histology revealed a significant increase in collagen fibril thickness at 12 weeks (P≤0.0001). No serious adverse effects., Conclusion: This study demonstrates improvement in facial skin health after topical HPE use, supported by collagen and elastin formation in the dermis. The product is well-tolerated, and participants were satisfied with the overall cosmetic outcome. J Drugs Dermatol. 2024;23(9):735-740. doi:10.36849/JDD.8162.

Background: Chronic wounds have been associated with an elevated burden of cellular senescence, a state of essentially irreversible cell cycle arrest, resistance to apoptosis, and a secretory phenotype. However, whether senescent cells contribute to wound chronicity in humans remains unclear. The objective of this article is to assess the role of clinicopathological characteristics and cellular senescence in the time-to-healing of chronic wounds., Methods: A cohort of 79 patients with chronic wounds was evaluated in a single-center academic practice from February 1, 2005, to February 28, 2015, and followed for up to 36 months. Clinical characteristics and wound biopsies were obtained at baseline, and time-to-healing was assessed. Wound biopsies were analyzed histologically for pathological characteristics and molecularly for markers of cellular senescence. In addition, biopsy slides were stained for p16 INK4a expression., Results: No clinical or pathological characteristics were found to have significant associations with time-to-healing. A Cox proportional hazard ratio model revealed increased CDKN1A (p21 CIP1/WAF1 ) expression to predict longer time-to-healing, and a model adjusted for gender and epidermal hyperplasia revealed increased CDKN1A expression and decreased PAPPA expression to predict longer time-to-healing. Increased p16 INK4a staining was observed in diabetic wounds compared to non-diabetic wounds, and the same association was observed in the context of high dermal fibrosis., Conclusions: The findings of this pilot study suggest that senescent cells contribute to wound chronicity in humans, especially in diabetic wounds., (© 2024 the International Society of Dermatology.)

Exosomes, or extracellular vesicles, represent the latest cell-free addition to the regenerative medicine toolkit. In vitro preclinical studies have demonstrated the safety and efficacy of exosomes, which vary based on source and biomanufacturing, for a myriad of potential therapeutic applications relevant to skin and soft tissue reconstruction. Primary search was performed in September 2021 on the MEDLINE database via PubMed and Ovid, with focus on articles about therapeutic application of exosomes or extracellular vesicles. In total, 130 articles met criteria for applicability, including early-stage clinical trials, preclinical research studies with in vivo application, and articles applicable to plastic and reconstructive surgery and dermatology. Most studies used animal models of human disease processes, using either animal donor cells to isolate exosomes, or human donor cells in animal models. Exosome technology has catapulted as an acellular therapeutic vehicle with off-the-shelf accessibility. These features eliminate prior threshold for broad adoption of regenerative cell-based therapies into surgical and medical practice. To date, there are no exosome products approved by the US Food and Drug Administration. This review highlights exosomes as the new frontier in regenerative medicine and outlines its preclinical therapeutic applications for cutaneous repair and restoration., Competing Interests: Dr. Rohrich receives instrument royalties from Eriem Surgical, Inc., and book royalties from Thieme Medical Publishing; is a clinical and research study expert for Allergan, Inc., Galderma, and MTF Biologics and a medical monitor for Merz North America; and owns Medical Seminars of Texas, LLC. Dr. Behfar is the founder and on the board of directors for Rion, Inc. Dr. Paradise is an employee of Rion, Inc. Dr. Wyles is consultant for Rion, Inc. Dr. McGraw and Erin Wilson have no financial interest to declare in relation to the content of this article.The authors have no financial interest to declare in relation to the content of this article., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The American Society of Plastic Surgeons.)

Background: Current strategies for hypertrophic scar prevention and treatment are limited., Objective: To facilitate these efforts, a minimally invasive hypertrophic scar model was created in a rabbit ear for the first time based on previous methods used to induce ischemia., Methods: Six New Zealand white rabbits (12 ears total) were studied. First, ischemia was achieved by ligating the cranial artery, cranial vein and central artery, while preserving the caudal artery, caudal vein and central vein, respectively. The relative level of ischemia induced at time of surgery, both baseline and maximum perfusion, was assessed with a fluorescent light-assisted angiography and demonstrated lower rates of perfusion in the ischemic ears. Following vascular injury, a 2-cm full thickness linear wound was created on the ventral ear and closed with 4 - 0 Nylon sutures under high tension. For each rabbit, one ear received a combination of ischemia and wounding with suture tension (n = 6), while the other ear was non-ischemic with wounding and suture tension alone (n = 6)., Results: Four weeks post-operatively, ischemic ears developed scar hypertrophy (histological scar thickness: 1.1 ± 0.2 mm versus 0.5 ± 0.1 mm, p < 0.05)., Conclusion: Herein, we describe a novel, prototypical minimally invasive rabbit ear model of hypertrophic scar formation that can allow investigation of new drugs for scar prevention., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Summary: Despite concerns from 1980s case reports, oral isotretinoin, a derivative of Vitamin A, has largely proven to be safe in surgical procedures with the exception of deep skin resurfacing. Isotretinoin modulates thinning skin and internal scarring in select rhinoplasty patients who may otherwise have poor definition and excessive scarring. A review of patients undergoing surgical interventions including rhinoplasty in the setting of concomitant isotretinoin was performed to examine safety and therapeutic potential. Forty-nine studies were reviewed. Isotretinoin use appears to be safe in a wide variety of surgical procedures relying on internal scar formation. In rhinoplasty, studies utilized oral isotretinoin to thin skin and improve appearance, patient and surgeon satisfaction. As such, the clinical potential for using oral isotretinoin in select rhinoplasty candidates such as those with thick glaborous sebaceous skin, ethnic, male, and/or revision patients, could mitigate internal scarring processes. Further studies examining the optimal dosing regimen and long-term benefits are warranted., (Copyright © 2024 by the American Society of Plastic Surgeons.)

Cellular senescence, a cell fate defined by irreversible cell cycle arrest, has been observed to contribute to chronic age-related conditions including non-healing wounds, such as diabetic foot ulcers. However, the role of cellular senescence in the pathogenesis of diabetic foot ulcers remains unclear. To examine the contribution of senescent phenotypes to these chronic wounds, differential gene and network analyses were performed on publicly available bulk RNA sequencing of whole skin biopsies of wound edge diabetic foot ulcers and uninvolved diabetic foot skin. Wald tests with Benjamini-Hochberg correction were used to evaluate differential gene expression. Results showed that cellular senescence markers, CDKN1A, CXCL8, IGFBP2, IL1A, MMP10, SERPINE1, and TGFA, were upregulated, while TP53 was downregulated in diabetic foot ulcers compared to uninvolved diabetic foot skin. NetDecoder was then used to identify and compare context-specific protein-protein interaction networks using known cellular senescence markers as pathway sources. The diabetic foot ulcer protein-protein interaction network demonstrated significant perturbations with decreased inhibitory interactions and increased senescence markers compared to uninvolved diabetic foot skin. Indeed, TP53 (p53) and CDKN1A (p21) appeared to be key regulators in diabetic foot ulcer formation. These findings suggest that cellular senescence is an important mediator of diabetic foot ulcer pathogenesis., (© 2023. The Author(s), under exclusive licence to American Aging Association.)

Hypertrophic scarring is a potential consequence of wound healing that causes functional and aesthetic disability. Common treatments include intralesional pharmacotherapy (e.g., triamcinolone), surgical excision, and energy-based laser devices. While numerous treatment methods have been described for hypertrophic scarring, an optimal treatment strategy has yet to be established given variability in clinical presentation. This study aims to identify patient- and provider-preferred treatment patterns. This is a single-center, retrospective study of adult patients that developed post-surgical hypertrophic scarring between 2007 and 2017. Specifically, trends in procedural management for hypertrophic scarring among this cohort were examined. A total of 442 procedures (intralesional steroid injection, surgical excision, laser-based treatment) were identified in 218 patients with a clinical diagnosis of hypertrophic scarring. Approximately 73% were female; 87% were Caucasian. The median age at first procedure was 45.6 years (SD = 17.4). The most frequent anatomical locations for procedures were the trunk (n = 242; 54.8%), followed by head/neck (n = 86; 19.5%), upper extremities (n = 67; 15.2%), and lower extremities (n = 45; 10.2%). Procedural therapies included intralesional steroid injection (n = 221; 50%), surgical excision (n = 112; 25.3%) and laser (fractional non-ablative laser vs. pulsed dye laser; n = 109; 24.5%). Treatment modality varied by stage of treatment, scar anatomical location, and scar size. This single-center series of patients with hypertrophic scarring highlights a patient-centered management approach and offers clinical guidelines for provider-patient shared decision making., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: As the largest organ in the human body, the skin is continuously exposed to intrinsic and extrinsic stimuli that impact its functionality and morphology with aging. Skin aging entails dysregulation of skin cells and loss, fragmentation, or fragility of extracellular matrix fibers that are manifested macroscopically by wrinkling, laxity, and pigmentary abnormalities. Age-related skin changes are the focus of many surgical and nonsurgical treatments aimed at improving overall skin appearance and health., Summary: As a hallmark of aging, cellular senescence, an essentially irreversible cell cycle arrest with apoptosis resistance and a secretory phenotype, manifests across skin layers by affecting epidermal and dermal cells. Knowledge of skin-specific senescent cells, such as melanocytes (epidermal aging) and fibroblasts (dermal aging), will promote our understanding of age-related skin changes and how to optimize patient outcomes in esthetic procedures., Key Messages: This review provides an overview of skin aging in the context of cellular senescence and discusses senolytic intervention strategies to selectively target skin senescent cells that contribute to premature skin aging., (© 2023 S. Karger AG, Basel.)

Competing Interests: None.

Malignant skin tumors in the setting of chronic leg ulcers (CLUs) are often underdiagnosed which may contribute to treatment delay and poor outcomes. The aims of our study were to determine the incidence and clinical characteristics of skin cancers in leg ulcers in the Olmsted County population from 1995 to 2020. We used the Rochester Epidemiology Project (a collaboration between health care providers) infrastructure to describe this epidemiology, allowing "population-based" research. Electronic medical records of adult patients with International Classification of Diseases diagnosis codes for leg ulcers and skin cancers on the legs were queried. Thirty-seven individuals with skin cancers in nonhealing ulcers were identified. The cumulative incidence of skin cancer over the 25-year period was 37:7864 (0.47%). The overall incidence rate was 470 per 100,000 patients. Eleven (29.7%) men and 26 (70.3%) women were identified with mean age of 77 years. History of venous insufficiency was present in 30 (81.1%) patients and diabetes in 13 (35.1%) patients. Clinical characteristics of CLU with skin cancer included abnormal granulation tissue in 36 (94.7%) and irregular borders in 35 (94.6%) cases. Skin cancers among CLUs included 17 (41.5%) basal cell carcinomas, 17 (41.5%) squamous cell carcinomas, 2 (4.9%) melanomas, 2 (4.9%) porocarcinomas, 1 (2.4%) basosquamous cell carcinoma, and 1 (2.4%) eccrine adenocarcinoma. The apparent association between chronic wounds and subsequent biopsy-proven skin cancer of the same site was primarily observed in elderly patients; malignant transformation of wounds favored basal cell carcinoma and squamous cell carcinoma. This retrospective cohort study further characterizes the association between skin cancers and chronic leg wounds., (Copyright © 2023 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Human lifespan continues to extend as an unprecedented number of people reach their seventh and eighth decades of life, unveiling chronic conditions that affect the older adult. Age-related skin conditions include senile purpura, seborrheic keratoses, pemphigus vulgaris, bullous pemphigoid, diabetic foot wounds and skin cancer. Current methods of drug testing prior to clinical trials require the use of pre-clinical animal models, which are often unable to adequately replicate human skin response. Therefore, a reliable model for aged human skin is needed. The current challenges in developing an aged human skin model include the intrinsic variability in skin architecture from person to person. An ideal skin model would incorporate innate functionality such as sensation, vascularization and regeneration. The advent of 3D bioprinting allows us to create human skin equivalent for use as clinical-grade surgical graft, for drug testing and other needs. In this review, we describe the process of human skin aging and outline the steps to create an aged skin model with 3D bioprinting using skin cells (i.e. keratinocytes, fibroblasts and melanocytes). We also provide an overview of current bioprinted skin models, associated limitations and direction for future research., (© The Author(s) 2023. Published by Oxford University Press.)

Despite the growing interest by researchers into cellular senescence, a hallmark of cellular aging, its role in human skin remains equivocal. The skin is the largest and most accessible human organ, reacting to the external and internal environment. Hence, it is an organ of choice to investigate cellular senescence and to target root-cause aging processes using senolytic and senomorphic agents, including naturally occurring plant-based derivatives. This review presents different aspects of skin cellular senescence, from physiology to pathology and signaling pathways. Cellular senescence can have both beneficial and detrimental effects on the skin, indicating that both prosenescent and antisenescent therapies may be desirable, based on the context. Knowledge of molecular mechanisms involved in skin cellular senescence may provide meaningful insights for developing effective therapeutics for senescence-related skin disorders, such as wound healing and cosmetic skin aging changes., (© 2023 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Wound healing is an essential physiological process for restoring normal skin structure and function post-injury. The role of cellular senescence, an essentially irreversible cell cycle state in response to damaging stimuli, has emerged as a critical mechanism in wound remodeling. Transiently-induced senescence during tissue remodeling has been shown to be beneficial in the acute wound healing phase. In contrast, persistent senescence, as observed in chronic wounds, contributes to delayed closure. Herein we describe a chronic wound murine model and its cellular senescence profile, including the senescence-associated secretory phenotype.

Background: Therapeutic interventions that optimize angiogenic activities may reduce rates of end-stage kidney disease, critical limb ischemia, and lower extremity amputations in individuals with diabetic kidney disease (DKD). Infusion of autologous mesenchymal stromal cells (MSC) is a promising novel therapy to rejuvenate vascular integrity. However, DKD-related factors, including hyperglycemia and uremia, might alter MSC angiogenic repair capacity in an autologous treatment approach., Methods: To explore the angiogenic activity of MSC in DKD, the transcriptome of adipose tissue-derived MSC obtained from DKD subjects was compared to age-matched controls without diabetes or kidney impairment. Next-generation RNA sequencing (RNA-seq) was performed on MSC (DKD n = 29; Controls n = 9) to identify differentially expressed (DE; adjusted p < 0.05, |log 2 fold change|> 1) messenger RNA (mRNA) and microRNA (miRNA) involved in angiogenesis (GeneCards). Paracrine-mediated angiogenic repair capacity of MSC conditioned medium (MSCcm) was assessed in vitro using human umbilical vein endothelial cells incubated in high glucose and indoxyl sulfate for a hyperglycemic, uremic state., Results: RNA-seq analyses revealed 133 DE mRNAs (77 upregulated and 56 down-regulated) and 208 DE miRNAs (119 up- and 89 down-regulated) in DKD-MSC versus Control-MSC. Interestingly, miRNA let-7a-5p, which regulates angiogenesis and participates in DKD pathogenesis, interacted with 5 angiogenesis-associated mRNAs (transgelin/TAGLN, thrombospondin 1/THBS1, lysyl oxidase-like 4/LOXL4, collagen 4A1/COL4A1 and collagen 8A1/COL8A1). DKD-MSCcm incubation with injured endothelial cells improved tube formation capacity, enhanced migration, reduced adhesion molecules E-selectin, vascular cell adhesion molecule 1 and intercellular adhesion molecule 1 mRNA expression in endothelial cells. Moreover, angiogenic repair effects did not differ between treatment groups (DKD-MSCcm vs. Control-MSCcm)., Conclusions: MSC from individuals with DKD show angiogenic transcriptome alterations compared to age-matched controls. However, angiogenic repair potential may be preserved, supporting autologous MSC interventions to treat conditions requiring enhanced angiogenic activities such as DKD, diabetic foot ulcers, and critical limb ischemia., (© 2023. The Author(s).)

Regenerative aesthetics is a burgeoning field for skin rejuvenation and skin health restoration. Exosomes, or extracellular vesicles, represent a new and minimally invasive addition to the regenerative aesthetic toolbox. These nano-sized vesicles contain bioactive cargo with crucial roles in intercellular communication. Exosome technology, while still in its infancy, is now leveraged in regenerative aesthetic medicine due to its multifaceted role in targeting root causes of skin aging and improving overall tissue homeostasis. The main considerations for practice utilization include variation in exosome purification, isolation, storage, scalability and reproducibility. This review aims at highlighting the current and emerging landscape of exosomes in aesthetic medicine including skin rejuvenation and hair restoration.

Androgenic alopecia (AGA) is a genetically predetermined condition that occurs as a result of stepwise miniaturization of the dermal papilla. During this process, the hair follicle suffers from increasing malnutrition and eventually dies, causing progressive hair loss. We recently highlighted that HIF-1α modulation may counteract hair loss. Here, we aim to demonstrate the positive influence of Tomorrowlabs HIF strengthening factor [HSF] hair restoration technology on hair biology in a monocentric blinded clinical trial over a total period of 9 months. A trial with 20 subjects (4 female and 16 male) and once-daily application of [HSF] hair restoration technology to the scalp was conducted. To assess the tolerability and efficacy of [HSF], testing included dermatological assessment, determination of hair loss by counting after combing, macro images of the head and TrichoScan evaluation of hair density as well as the proportion of anagen hair versus telogen hair. The clinical data show Tomorrowlabs [HSF] hair restoration to be safe and effective to counteract AGA. The use of Tomorrowlabs [HSF] hair restoration resulted in improvements in the clinical parameters of hair quality such as thickness (+7.2%), hair density (+14.3%) and shine and elasticity (+20.3%) during the test period. The effectiveness of the test product was further determined by a significant reduction in hair loss of an average of 66.8% in treatment-responsive subjects after 6 months and an increase in hair growth reaching up to 32.5%, with an average percentage change of 8.4% in all participants and 10.8% in the responsive patients (85% of the study cohort) after 9 months on TrichoScan evaluation. The hair growth cycle was harmonized with the result of an average anagen hair percentage increase of +8.0% and telogen hair percentage reduction of -14.0% shown in the test area. Applicable for both sexes in an alcohol-free formulation, beneficial to scalp health and free of complications or side effects, this novel product provides objectively measurable results counteracting hair loss paired with an improved look and feel of the hair.

Summary: Beyond the palliative reach of today's medicines, medical therapies of tomorrow aim to treat the root cause of age-related diseases by targeting fundamental aging mechanisms. Pillars of aging include, among others, genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, dysregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. The unitary theory of fundamental aging processes posits that by targeting one fundamental aging process, it may be feasible to impact several or all others given its interdependence. Indeed, pathologic accumulation of senescent cells is implicated in chronic diseases and age-associated morbidities, suggesting that senescent cells are a good target for whole-body aging intervention. Preclinical studies using senolytics, agents that selectively eliminate senescent cells, and senomorphics, agents that inhibit production or release of senescence-associated secretory phenotype factors, show promise in several aging and disease preclinical models. Early clinical trials using a senolytic combination (dasatinib and quercetin), and other senolytics including flavonoid, fisetin, and BCL-xL inhibitors, illustrate the potential of senolytics to alleviate age-related dysfunction and diseases including wound healing. Translation into clinical applications requires parallel clinical trials across institutions to validate senotherapeutics as a vanguard for delaying, preventing, or treating age-related disorders and aesthetic aging., Competing Interests: Disclosure: Patents on senolytic drugs are held by the Mayo Clinic. Dr. Wyles has a nonrelevant financial interest in Rion Aesthetics LLC. The authors have no financial interest to declare in relation to the content of this article. This research has been reviewed by the Mayo Clinic Conflict of Interest Review Board and was conducted in compliance with Mayo Clinic conflict of interest policies., (Copyright © 2022 by the American Society of Plastic Surgeons.)

Background: Exosomes are regenerative mediators for skin rejuvenation. Human platelet extract (HPE) is an allogeneic exosome product derived from US-sourced, leukocyte-reduced apheresed platelets with consistent purity and potency., Objectives: The authors sought to better characterize the safety and tolerability of novel HPE (plated) Intensive Repair Serum (Rion Aesthetics, Rochester, MN) and its maximal effects on skin rejuvenation at 6 weeks., Methods: This prospective, single-arm, non-randomized, longitudinal study investigated the safety and efficacy of HPE. Structured sub-analysis evaluated multifactorial improvement in skin health following standardized skin care regimen to determine the maximal effect. Evaluation at baseline and 6 weeks included participant questionnaires and photo documentation with VISIA-CR Generation 5 3D PRIMOS (Canfield Scientific Inc, Fairfield, NJ)., Results: VISIA-CR imaging yielded quantifiable and statistically significant improvements in overall skin health (skin health score). A greater score correlated to greater overall skin health, and there was a statistically significant mean delta improvement of 224.2 ± 112.8 (mean ± standard deviation, P ≤ 0.0001) in skin health score at 6 weeks compared with baseline. This correlated to reduction in redness, wrinkles, and melanin production across all cosmetic units (P = 0.005, P = 0.0023, P ≤ 0.0001, respectively) and significant improvements in luminosity and color evenness (P ≤ 0.001)., Conclusions: A topically applied platelet-derived exosome product, HPE, induced normalization to skin health at 4 to 6 weeks with improved various clinical measures of facial photodamage and cutaneous aging. It is safe, well-tolerated, and well-liked by participants., (© The Author(s) 2022. Published by Oxford University Press on behalf of The Aesthetic Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Keloid scar formation arises from a disorganized fibroproliferative collagen response that extends beyond the original wound margins because of excessive production of extracellular matrix (ECM). Despite treatment options for keloid scars including medical and surgical therapies, such as intralesional steroid injection and surgical excision, the recurrence rate remains high. Herein we consolidate recently published narrative reviews, systematic reviews, and meta-analyses to provide an overview of updated treatment recommendations for keloidal scar formation. PubMed search engine was used to access the MEDLINE database to investigate updates regarding keloid incidence and treatment. More than 100 articles were reviewed. Keloid management remains a multimodal approach. There continues to be no gold standard of treatment that provides a consistently low recurrence rate; however, the increasing number of available treatments and synergistic combinations of these treatments (i.e., laser-based devices in combination with intralesional steroids, or 5-fluorouracil (5-FU) in combination with steroid therapy) is showing favorable results. Future studies could target the efficacy of novel treatment modalities (i.e., autologous fat grafting or stem cell-based therapies) for keloid management. This review article provides updated treatment guidelines for keloids and discusses insight into management to assist patient-focused, evidence-based clinical decision making., (© 2020 the International Society of Dermatology.)

The biology of regenerative medicine has steadily matured, providing the foundation for randomized clinical trials and translation into validated applications. Today, the growing regenerative armamentarium is poised to impact disease management, yet a gap in training next-generation healthcare providers, equipped to adopt and deliver regenerative options, has been exposed. This special report highlights a multiyear experience in developing and deploying a comprehensive regenerative curriculum for medical trainees. For academicians and institutions invested in establishing a formalized regenerative medicine syllabus, the Regenerative Medicine and Surgery course provides a patient-focused prototype for next-generation learners, offering a dedicated educational experience that encompasses discovery, development and delivery of regenerative solutions. Built with the vision of an evolving regenerative care model, this transdisciplinary endeavor could serve as an adoptable education portal to advance the readiness of the emergent regenerative healthcare workforce globally.

Aim: Evaluate the clinical effectiveness of platelet-rich plasma as a treatment for lichen sclerosus., Methods: A systematic review was performed. The electronic databases PubMed, Ovid MEDLINE ® , Web of Science, Cochrane, clinicaltrials.gov were used to identify case studies, case series, prospective uncontrolled, and randomized controlled studies published between 1946 and April 21, 2021. Six prospective uncontrolled studies, one randomized double-blind prospective study, and one case report were included., Results: Platelet-rich plasma treatment was subjectively reported to improve quality of life, but objective measures demonstrating treatment efficacy were not observed. In addition, platelet-rich plasma preparation and administration between studies lacked standardization., Conclusion: Platelet-rich plasma may be used for symptomatic adjuvant treatment of lichen sclerosus, though additional double-blind controlled studies with standardized platelet-rich plasma protocols are needed to better characterize the efficacy of platelet-rich plasma., Competing Interests: Conflicts of interest All authors declared that there are no conflicts of interest relevant to this study.

Objective: To evaluate the impact of a novel interdisciplinary graduate-level course in chimeric antigenic receptor-T cell therapy on students' knowledge and interests in translational science., Materials/participants and Methods: The course ran November 12 to 16, 2018. Students were surveyed before and after the course. The survey included questions regarding background, self-perceived knowledge/confidence in skills, and interests/predicted behaviors. Students were assigned to work in collaborative interdisciplinary teams to develop a research proposal., Results: A total of 25 students taking the course for graduate-level credit were surveyed. Of these, all 25 (100%) completed the surveys. Students came from variable backgrounds and were at different stages of graduate training. After completion of the course, there was a statistically significant increase in self-perceived knowledge of immunotherapy (mean score of 3.6 postcourse vs 2.6 precourse, on a 5-point Likert scale; P <.001), knowledge of the bench to clinic translational process (3.7 postcourse vs 3.0 precourse; P <.001), confidence in critical reading skills (4.3 postcourse vs 4.0 precourse; P =.008), confidence in immunotherapy-focused grant writing skills (3.6 postcourse vs 2.8 precourse; P <.001), and interest in working in interdisciplinary teams (4.8 postcourse vs 4.6 precourse; P =.02)., Conclusion: The structure of this innovative and comprehensive course serves as a platform for educational courses in interdisciplinary translational research and helps trainees build knowledge and interest in the fields of chimeric antigenic receptor-T cells, regenerative sciences, and immunotherapy., (© 2019 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc.)

Regenerative sciences are poised to transform clinical practice. The quest for regenerative solutions has, however, exposed a major gap in current healthcare education. A call for evidence-based adoption has underscored the necessity to establish rigorous regenerative medicine educational programs early in training. Here, we present a patient-centric regenerative medicine curriculum embedded into medical school core learning. Launched as a dedicated portal of new knowledge, learner proficiency was instilled by means of a discovery-translation-application blueprint. Using the "from the patient to the patient" paradigm, student experience recognized unmet patient needs, evolving regenerative technologies, and ensuing patient management solutions. Targeted on the deployment of a regenerative model of care, complementary subject matter included ethics, regulatory affairs, quality control, supply chain, and biobusiness. Completion of learning objectives was monitored by online tests, group teaching, simulated clinical examinations along with longitudinal continuity across medical school training and residency. Success was documented by increased awareness and proficiency in domain-relevant content, as well as specialty identification through practice exposure, research engagement, clinical acumen, and education-driven practice advancement. Early incorporation into mainstream medical education offers a tool to train next-generation healthcare providers equipped to adopt and deliver validated regenerative medicine solutions., Competing Interests: The authors declare no competing interests.

Focal adhesion kinase (FAK) is an intensely studied non-receptor tyrosine kinase with roles in cancer and other common human diseases. Despite the large interest in FAK, the in vivo contribution of FAK auto-phosphorylation site tyrosine (Y) 397 to FAK function is incompletely understood. To study FAK Y397 in vivo we analyzed mice with 'non-phosphorylatable' Y-to-phenylalanine (F) and 'phospho-mimicking' Y-to-glutamate (E) mutations in the germline. We found that FAK Y397F mice die early during embryogenesis with abnormal angiogenesis like FAK kinase-dead mice. When Y397 is mutated to a glutamate mice survive beyond mid-gestation like mice where Y397 is lost by deletion of FAK exon 15. In culture, defects in proliferation, invasion and gene expression were more severe with the FAK Y397F than with the FAK Y397E mutation despite the inability of FAK Y397E to bind SRC. Conditional expression of FAK Y397F or Y397E in unchallenged avascular epidermis, however, resulted in no appreciable phenotype. We conclude that FAK Y397 is required for the highly dynamic tissue remodeling during development but dispensable for normal homeostasis of avascular epidermis. In contrast to the Y397F mutation, FAK Y397E retains sufficient biological activity to allow for development beyond mid-gestation., Competing Interests: The authors have declared that no competing interests exist.

Background: Atrial fibrillation is a cardiac disease driven by numerous idiopathic etiologies. NUP155 is a nuclear pore complex protein that has been identified as a clinical driver of atrial fibrillation, yet the precise mechanism is unknown. The present study employs a systems biology algorithm to identify effects of NUP155 disruption on cardiogenicity in a model of stem cell-derived differentiation., Methods: Embryonic stem (ES) cell lines (n = 5) with truncated NUP155 were cultured in parallel with wild type (WT) ES cells (n = 5), and then harvested for RNAseq. Samples were run on an Illumina HiSeq 2000. Reads were analyzed using Strand NGS, Cytoscape, DAVID and Ingenuity Pathways Analysis to deconvolute the NUP155-disrupted transcriptome. Network topological analysis identified key features that controlled framework architecture and functional enrichment., Results: In NUP155 truncated ES cells, significant expression changes were detected in 326 genes compared to WT. These genes segregated into clusters that enriched for specific gene ontologies. Deconvolution of the collective framework into discrete sub-networks identified a module with the highest score that enriched for Cardiovascular System Development, and revealed NTRK1/TRKA and SRSF2/SC35 as critical hubs within this cardiogenic module., Conclusions: The strategy of pluripotent transcriptome deconvolution used in the current study identified a novel association of NUP155 with potential drivers of arrhythmogenic AF. Here, NUP155 regulates cardioplasticity of a sub-network embedded within a larger framework of genome integrity, and exemplifies how transcriptome cardiogenicity in an embryonic stem cell genome is recalibrated by nucleoporin dysfunction.

Background: Arthroplasty implants commonly contain elemental metal that may undergo wear-related release. Recently, cases of hip implant-associated myocardial injury have been reported. However, we are not aware of any previous study that has systematically measured myocardial metal levels or examined the relationship with total hip arthroplasty (THA)., Methods: Archives of our institution were queried for autopsies of individuals who had undergone THA between 1990 and 2013. Myocardial tissue samples were analyzed for cobalt (Co) and chromium (Cr) levels with inductively coupled plasma mass spectroscopy. Seventy-five Co/Cr-on-polyethylene THA cases were included (mean age at time of death = 77.4 years; 49% women) as were 73 non-arthroplasty controls matched for age, sex, and history of hypertension and diabetes mellitus., Results: Significantly higher median myocardial concentrations of Co were observed in individuals with THA compared with controls (0.12 versus 0.06 μg/g, p < 0.0001). The median Co concentration was 69% higher in patients who had undergone THA revision (0.169 μg/g) than in those who underwent primary THA (0.100 μg/g; p = 0.004). In general, higher Co levels were observed in those with multiple replaced joints, although this finding only trended toward significance. Cardiomegaly, interstitial fibrosis, and decreased ejection fraction were observed more frequently in the postmortem samples of patients with implants than in those of controls (p = 0.0002, 0.044, and 0.0039, respectively)., Conclusions: We believe this to be the first study to quantify metal levels in cardiac tissue in patients with and without joint replacement. The elevated Co levels, in concert with cardiomegaly and increased interstitial fibrosis found during autopsy, in the arthroplasty cohort are novel, important findings. Although Co levels were significantly elevated above those in controls, the majority were below those seen in clinical case reports of death from Co cardiotoxicity associated with metal-on-metal prostheses., Level of Evidence: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase involved in development and human disease, including cancer. It is currently thought that the four-point one, ezrin, radixin, moesin (FERM)-kinase domain linker, which contains autophosphorylation site tyrosine (Y) 397, is not required for in vivo FAK function until late midgestation. Here, we directly tested this hypothesis by generating mice with FAK Y397-to-phenylalanine (F) mutations in the germline. We found that Y397F embryos exhibited reduced mesodermal fibronectin (FN) and osteopontin expression and died during mesoderm development akin to FAK kinase-dead mice. We identified myosin-1E (MYO1E), an actin-dependent molecular motor, to interact directly with the FAK FERM-kinase linker and induce FAK kinase activity and Y397 phosphorylation. Active FAK in turn accumulated in the nucleus where it led to the expression of osteopontin and other FN-type matrix in both mouse embryonic fibroblasts and human melanoma. Our data support a model in which FAK Y397 autophosphorylation is required for FAK function in vivo and is positively regulated by MYO1E.

Calreticulin deficiency causes myocardial developmental defects that culminate in an embryonic lethal phenotype. Recent studies have linked loss of this calcium binding chaperone to failure in myofibrillogenesis through an as yet undefined mechanism. The purpose of the present study was to identify cellular processes corrupted by calreticulin deficiency that precipitate dysregulation of cardiac myofibrillogenesis related to acquisition of cardiac phenotype. In an embryonic stem cell knockout model, calreticulin deficit (crt(-/-)) compromised nucleocytoplasmic transport of nuclear localization signal-dependent and independent pathways, disrupting nuclear import of the cardiac transcription factor MEF2C. The expression of nucleoporins and associated nuclear transport proteins in derived crt(-/-) cardiomyocytes revealed an abnormal nuclear pore complex (NPC) configuration. Altered protein content in crt(-/-) cells resulted in remodeled NPC architecture that caused decreased pore diameter and diminished probability of central channel occupancy versus wild type counterparts. Ionophore treatment of impaired calcium handling in crt(-/-) cells corrected nuclear pore microarchitecture and rescued nuclear import resulting in normalized myofibrillogenesis. Thus, calreticulin deficiency alters nuclear pore function and structure, impeding myofibrillogenesis in nascent cardiomyocytes through a calcium dependent mechanism. This essential role of calreticulin in nucleocytoplasmic communication competency ties its regulatory action with proficiency of cardiac myofibrillogenesis essential for proper cardiac development., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Local infiltration analgesia and peripheral nerve blocks are common methods for pain management in patients after THA but direct head-to-head, randomized controlled trials (RCTs) have not been performed. A network meta-analysis allows indirect comparison of individual treatments relative to a common comparator; in this case placebo (or no intervention), epidural analgesia, and intrathecal morphine, yielding an estimate of comparative efficacy., Questions/purposes: We asked, when compared with a placebo, (1) does use of local infiltration analgesia reduce patient pain scores and opioid consumption, (2) does use of peripheral nerve blocks reduce patient pain scores and opioid consumption, and (3) is local infiltration analgesia favored over peripheral nerve blocks for postoperative pain management after THA?, Methods: We searched six databases, from inception through June 30, 2014, to identify RCTs comparing local infiltration analgesia or peripheral nerve block use in patients after THA. A total of 35 RCTs at low risk of bias based on the recommended Cochrane Collaboration risk assessment tool were included in the network meta-analysis (2296 patients). Primary outcomes for this review were patient pain scores at rest and cumulative opioid consumption, both assessed at 24 hours after THA. Because of substantial heterogeneity (variation of outcomes between studies) across included trials, a random effect model for meta-analysis was used to estimate the weighted mean difference (WMD) and 95% CI. The gray literature was searched with the same inclusion criteria as published trials. Only one unpublished trial (published abstract) fulfilled our criteria and was included in this review. All other studies included in this systematic review were full published articles. Bayesian network meta-analysis included all RCTs that compared local infiltration analgesia or peripheral nerve blocks with placebo (or no intervention), epidural analgesia, and intrathecal morphine., Results: Compared with placebo, local infiltration analgesia reduced patient pain scores (WMD, -0.61; 95% CI, -0.97 to -0.24; p = 0.001) and opioid consumption (WMD, -7.16 mg; 95% CI, -11.98 to -2.35; p = 0.004). Peripheral nerve blocks did not result in lower pain scores or reduced opioid consumption compared with placebo (WMD, -0.43; 95% CI, -0.99 to 0.12; p = 0.12 and WMD, -3.14 mg, 95% CI, -11.30 to 5.02; p = 0.45). However, network meta-analysis comparing local infiltration analgesia with peripheral nerve blocks through common comparators showed no differences between postoperative pain scores (WMD, -0.36; 95% CI, -1.06 to 0.31) and opioid consumption (WMD, -4.59 mg; 95% CI, -9.35 to 0.17), although rank-order analysis found local infiltration analgesia to be ranked first in more simulations than peripheral nerve blocks, suggesting that it may be more effective., Conclusions: Using the novel statistical network meta-analysis approach, we found no differences between local infiltration analgesia and peripheral nerve blocks in terms of analgesia or opioid consumption 24 hours after THA; there was a suggestion of a slight advantage to peripheral nerve blocks based on rank-order analysis, but the effect size in question is likely not large. Given the slight difference between interventions, clinicians may choose to focus on other factors such as cost and intervention-related complications when debating which analgesic treatment to use after THA., Level of Evidence: Level I, therapeutic study.

Dilated cardiomyopathy (DCM) is a leading cause of heart failure. In families with autosomal-dominant DCM, heterozygous missense mutations were identified in RNA-binding motif protein 20 (RBM20), a spliceosome protein induced during early cardiogenesis. Dermal fibroblasts from two unrelated patients harboring an RBM20 R636S missense mutation were reprogrammed to human induced pluripotent stem cells (hiPSCs) and differentiated to beating cardiomyocytes (CMs). Stage-specific transcriptome profiling identified differentially expressed genes ranging from angiogenesis regulator to embryonic heart transcription factor as initial molecular aberrations. Furthermore, gene expression analysis for RBM20-dependent splice variants affected sarcomeric (TTN and LDB3) and calcium (Ca(2+)) handling (CAMK2D and CACNA1C) genes. Indeed, RBM20 hiPSC-CMs exhibited increased sarcomeric length (RBM20: 1.747 ± 0.238 µm versus control: 1.404 ± 0.194 µm; P < 0.0001) and decreased sarcomeric width (RBM20: 0.791 ± 0.609 µm versus control: 0.943 ± 0.166 µm; P < 0.0001). Additionally, CMs showed defective Ca(2+) handling machinery with prolonged Ca(2+) levels in the cytoplasm as measured by greater area under the curve (RBM20: 814.718 ± 94.343 AU versus control: 206.941 ± 22.417 AU; P < 0.05) and higher Ca(2+) spike amplitude (RBM20: 35.281 ± 4.060 AU versus control:18.484 ± 1.518 AU; P < 0.05). β-adrenergic stress induced with 10 µm norepinephrine demonstrated increased susceptibility to sarcomeric disorganization (RBM20: 86 ± 10.5% versus control: 40 ± 7%; P < 0.001). This study features the first hiPSC model of RBM20 familial DCM. By monitoring human cardiac disease according to stage-specific cardiogenesis, this study demonstrates RBM20 familial DCM is a developmental disorder initiated by molecular defects that pattern maladaptive cellular mechanisms of pathological cardiac remodeling. Indeed, hiPSC-CMs recapitulate RBM20 familial DCM phenotype in a dish and establish a tool to dissect disease-relevant defects in RBM20 splicing as a global regulator of heart function., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Pathological cardiac development is precipitated by dysregulation of calreticulin, an endoplasmic reticulum (ER)-resident calcium binding chaperone and critical contributor to cardiogenesis and embryonic viability. However, pleiotropic phenotype derangements induced by calreticulin deficiency challenge the identification of specific downstream transcriptome elements that direct proper cardiac formation. Here, differential transcriptome navigation was used to diagnose high priority calreticulin domain-specific gene expression changes and decrypt complex cardiac-specific molecular responses elicited by discrete functional regions of calreticulin., Methods: Wild type (WT), calreticulin-deficient (CALR(-/-)), and calreticulin truncation variant (CALR(-/-)-NP and CALR(-/-)-PC) pluripotent stem cells were used to investigate molecular remodeling underlying a model of cardiopathology. Bioinformatic deconvolution of isolated transcriptomes was performed to identify predominant expression trends, gene ontology prioritizations, and molecular network features characteristic of discrete cell types., Results: Stem cell lines with wild type (WT), calreticulin-deficient (CALR(-/-)) genomes, as well as calreticulin truncation variants exclusively expressing either the chaperoning (CALR(-/-)-NP) or the calcium binding (CALR(-/-)-PC) domain exhibited characteristic molecular signatures determined by unsupervised agglomerative clustering. Kohonen mapping of RNA expression changes identified transcriptome dynamics that segregated into 12 discrete gene expression meta-profiles which were enriched for regulation of Eukaryotic Initiation Factor 2 (EIF2) signaling. Focused examination of domain-specific gene ontology remodeling revealed a general enrichment of Cardiovascular Development in the truncation variants, with unique prioritization of "Cardiovascular Disease" exclusive to the cohort of down regulated genes of the PC truncation variant. Molecular cartography of genes that comprised this cardiopathological category revealed uncharacterized and novel gene relationships, with identification of Pitx2 as a critical hub within the topology of a CALR(-/-) compromised network., Conclusions: Diagnostic surveillance, through an algorithm that integrates pluripotent stem cell transcriptomes with advanced high throughput assays and computational bioinformatics, revealed collective gene expression network changes that underlie differential phenotype development. Stem cell transcriptomes provide a deep collective molecular index that reflects ad hoc robustness of the pluripotent gene network. Remodeling events such as monogenic lesions provide a background by which high priority candidate disease effectors and regulators can be identified, demonstrated here by a molecular profiling algorithm that decrypts pluripotent wild type versus disrupted genomes.

Over the last decade, advancements in stem cell biology have yielded a variety of sources for stem cell-based cardiovascular investigation. Stem cell behavior, whether to maintain its stable state of pluripotency or to prime toward the cardiovascular lineage is governed by a set of coordinated interactions between epigenetic, transcriptional, and translational mechanisms. The science of incorporating genes (genomics), RNA (transcriptomics), proteins (proteomics), and metabolites (metabolomics) data in a specific biological sample is known as systems biology. Integrating systems biology in progression with stem cell biologics can contribute to our knowledge of mechanisms that underlie pluripotency maintenance and guarantee fidelity of cardiac lineage specification. This review provides a brief summarization of OMICS-based strategies including transcriptomics, proteomics, and metabolomics used to understand stem cell fate and to outline molecular processes involved in heart development. Additionally, current efforts in cardioregeneration based on the "one-size-fits-all" principle limit the potential of individualized therapy in regenerative medicine. Here, we summarize recent studies that introduced systems biology into cardiovascular clinical outcomes analysis, allowing for predictive assessment for disease recurrence and patient-specific therapeutic response.

Background: Cardiac resynchronization therapy using bi-ventricular pacing is proven effective in the management of heart failure (HF) with a wide QRS-complex. In the absence of QRS prolongation, however, device-based resynchronization is reported unsuitable. As an alternative, the present study tests a regenerative cell-based approach in the setting of narrow QRS-complex HF., Methods and Results: Progressive cardiac dyssynchrony was provoked in a chronic transgenic model of stress-triggered dilated cardiomyopathy. In contrast to rampant end-stage disease afflicting untreated cohorts, stem cell intervention early in disease, characterized by mechanical dyssynchrony and a narrow QRS-complex, aborted progressive dyssynchronous HF and prevented QRS widening. Stem cell-treated hearts acquired coordinated ventricular contraction and relaxation supporting systolic and diastolic performance. Rescue of contractile dynamics was underpinned by a halted left ventricular dilatation, limited hypertrophy, and reduced fibrosis. Reverse remodeling reflected a restored cardiomyopathic proteome, enforced at systems level through correction of the pathological molecular landscape and nullified adverse cardiac outcomes. Cell therapy of a dyssynchrony-prone cardiomyopathic cohort translated prospectively into improved exercise capacity and prolonged survivorship., Conclusions: In narrow QRS HF, a regenerative approach demonstrated functional and structural benefit, introducing the prospect of device-autonomous resynchronization therapy for refractory disease., (© 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Background: Corticosteroids are a common, short-term, local antiinflammatory and analgesic for treating patients with musculoskeletal disorders. Studies have shown the deleterious effects of corticosteroids on chondrocytes, suggesting a potentiation of degenerative joint disease. Mesenchymal stem cells (MSCs) are the direct progenitors of chondrocytes and other musculoskeletal tissue. Additionally, they serve an important antiinflammatory role, which can combat the chronic inflammatory state that mediates degenerative joint disease. Little is known about how corticosteroids interact with this regenerative and reparative cell population., Questions/purposes: We asked: (1) Are corticosteroids cytotoxic to MSCs in a dose-response fashion? (2) Is there a differential effect in the level of cytotoxicity to MSCs between commercially available corticosteroid preparations?, Methods: Human MSCs were isolated and cultured from periarticular adipose tissue obtained from 20 patients undergoing primary THA. MSCs were exposed for 60 minutes to one of four commonly used corticosteroid preparations: betamethasone sodium phosphate-betamethasone acetate (6 mg/mL), dexamethasone sodium phosphate (4 mg/mL), methylprednisolone (40 mg/mL), or triamcinolone acetonide (40 mg/mL). Among the four preparations (treatment groups), cells were exposed to increasing concentrations of drugs according to the following titrations of the commercially available preparation: 0.0 (control solution of 1X phosphate buffered saline), 3.125, 6.25, 12.5, 25, 50, 75, and 100 % (undiluted commercial product). Cells were allowed to recover in standard culture media for 24 hours. After the recovery period, cell viability was measured using -(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) tetrazolium dye-based cellular viability assay and live-dead cell fluorescent staining. For the MTS assay, measurements were quantified in units of optical density (OD). ANOVA was performed at every experimental steroid concentration. When this global test was statistically significant, all pairwise comparisons were performed at that concentration with p values adjusted by the Tukey method to guard against Type I error., Results: Exposure to corticosteroids decreased MSC viability in a curvilinear dose-response pattern. For betamethasone, the mean MTS OD at 0% steroid concentration was 1.03 (SD, 0.12) and decreased to 0.00 (SD, 0.00) at 25% steroid concentration. For dexamethasone, the mean MTS OD at 0% steroid concentration was 1.00 (SD, 0.07) and decreased to 0.00 (SD, 0.01) at 100% steroid concentration. For methylprednisolone, the mean MTS OD at 0% steroid concentration was 1.03 (SD, 0.09) and decreased to 0.00 (SD, 0.00) at 100% steroid concentration. For triamcinolone, the mean MTS OD at 0% steroid concentration was 1.02 (SD, 0.09) and decreased to 0.00 (SD, 0.00) at 75% steroid concentration. There were large differences among commercially available preparations, and these differences were present at every concentration. In general, dexamethasone was most gentle on MSCs (average OD by steroid concentration: 0% = 1.00; 3.125% = 0.86; 6.25% = 0.74; 12.5% = 0.53; 25% = 0.30; 50% = 0.20; 75% = 0.09; 100% = 0.00, triamcinolone and methylprednisolone were intermediate (triamcinolone average OD by steroid concentration: 0% = 1.02; 3.125% = 0.82; 6.25% = 0.64; 12.5% = 0.45; 25% = 0.18; 50% = 0.03; 75% = 0.00; 100% = 0.00; methylprednisolone average OD by steroid concentration: 0% = 1.03; 3.125% = 0.74; 6.25% = 0.54; 12.5% = 0.31; 25% = 0.12; 50% = 0.01; 75% = 0.00; 100% = 0.00), and betamethasone was most toxic (average OD by steroid concentration: 0% = 1.03; 3.125% = 0.74; 6.25% = 0.27; 12.5% = 0.02; 25% = 0.00; 50% = 0.00; 75% = 0.00; 100% = 0.00). ANOVA testing showed p values less than 0.0001 at every tested concentration (with the exception of the 0% control solution; p = 0.204) with subsequent pairwise comparisons supporting the relationships described above. The outcomes were maintained after stratifying by age, sex, or indication for THA (osteoarthritis versus avascular necrosis)., Conclusions: Commonly used intraarticular corticosteroids had a dose-dependent, profound, and differential effect on MSCs in this in vitro model, with betamethasone being the most toxic. Further studies are needed to assess if the in vitro effects of these agents translate into similar in vivo outcomes., Clinical Relevance: Corticosteroids frequently are used by physicians to reduce inflammation in patients with musculoskeletal disorders, but these agents may hinder MSCs' innate regenerative capacity in exchange for temporary analgesia. Our study suggests that choosing dexamethasone may result in less harmful effects when compared with other injectable steroids.