All Publications


  • A tension offloading patch mitigates dermal fibrosis induced by pro-fibrotic skin injections. Research square Talbott, H. E., Griffin, M. F., Mascharak, S., Parker, J. B., Kuhnert, M. M., Guo, J. L., Diaz Deleon, N. M., Lavin, C., Abbas, D., Guardino, N., Morgan, A., Valencia, C., Cotterell, A., Longaker, M. T., Wan, D. C. 2024

    Abstract

    Skin fibrosis is a clinical problem with devastating impacts but limited treatment options. In the setting of diabetes, insulin administration often causes local dermal fibrosis, leading to a range of clinical sequelae including impeded insulin absorption. Mechanical forces are important drivers of fibrosis and, clinically, physical tension offloading at the skin level using an elastomeric patch significantly reduces wound scarring. However, it is not known whether tension offloading could similarly prevent skin fibrosis in the setting of pro-fibrotic injections. Here, we develop a porcine model using repeated local injections of bleomycin to recapitulate key features of insulin-induced skin fibrosis. Using histologic, tissue ultrastructural, and biomechanical analyses, we show that application of a tension-offloading patch both prevents and rescues existing skin fibrosis from bleomycin injections. By applying single-cell transcriptomic analysis, we find that the fibrotic response to bleomycin involves shifts in myeloid cell dynamics from favoring putatively pro-regenerative to pro-fibrotic myeloid subtypes; in a mechanomodulatory in vitro platform, we show that these shifts are mechanically driven and reversed by exogenous IL4. Finally, using a human foreskin xenograft model, we show that IL4 treatment mitigates bleomycin-induced dermal fibrosis. Overall, this study highlights that skin tension offloading, using an FDA cleared, commercially available patch, could have significant potential clinical benefit for the millions of patients dependent on insulin.

    View details for DOI 10.21203/rs.3.rs-3915097/v1

    View details for PubMedID 38464040

  • Allele-specific expression reveals genetic drivers of tissue regeneration in mice. Cell stem cell Mack, K. L., Talbott, H. E., Griffin, M. F., Parker, J. B., Guardino, N. J., Spielman, A. F., Davitt, M. F., Mascharak, S., Downer, M., Morgan, A., Valencia, C., Akras, D., Berger, M. J., Wan, D. C., Fraser, H. B., Longaker, M. T. 2023

    Abstract

    In adult mammals, skin wounds typically heal by scarring rather than through regeneration. In contrast, "super-healer" Murphy Roths Large (MRL) mice have the unusual ability to regenerate ear punch wounds; however, the molecular basis for this regeneration remains elusive. Here, in hybrid crosses between MRL and non-regenerating mice, we used allele-specific gene expression to identify cis-regulatory variation associated with ear regeneration. Analyzing three major cell populations (immune, fibroblast, and endothelial), we found that genes with cis-regulatory differences specifically in fibroblasts were associated with wound-healing pathways and also co-localized with quantitative trait loci for ear wound-healing. Ectopic treatment with one of these proteins, complement factor H (CFH), accelerated wound repair and induced regeneration in typically fibrotic wounds. Through single-cell RNA sequencing (RNA-seq), we observed that CFH treatment dramatically reduced immune cell recruitment to wounds, suggesting a potential mechanism for CFH's effect. Overall, our results provide insights into the molecular drivers of regeneration with potential clinical implications.

    View details for DOI 10.1016/j.stem.2023.08.010

    View details for PubMedID 37714154

  • Multiplexed evaluation of mouse wound tissue using oligonucleotide barcoding with single-cell RNA sequencing. STAR protocols Januszyk, M., Griffin, M., Mascharak, S., Talbott, H. E., Chen, K., Henn, D., Spielman, A. F., Parker, J. B., Liang, N. E., Cotterell, A., Guardino, N., Foster, D. S., Wagh, D., Coller, J., Gurtner, G. C., Wan, D. C., Longaker, M. T. 2022; 4 (1): 101946

    Abstract

    Despite its rapidly increased availability for the study of complex tissue, single-cell RNA sequencing remains prohibitively expensive for large studies. Here, we present a protocol using oligonucleotide barcoding for the tagging and pooling of multiple samples from healing wounds, which are among the most challenging tissue types for this application. We describe steps to generate skin wounds in mice, followed by tissue harvest and oligonucleotide barcoding. This protocol is also applicable to other species including rats, pigs, and humans. For complete details on the use and execution of this protocol, please refer to Stoeckius etal. (2018),1 Galiano etal. (2004),2 and Mascharak etal. (2022).3.

    View details for DOI 10.1016/j.xpro.2022.101946

    View details for PubMedID 36525348

  • Inhibition of Yes-Associated Protein Promotes Skin Wound Regeneration in Large Animals Januszyk, M., Talbott, H. E., Griffin, M., Guardino, N., Spielman, A., Guo, J. L., Mascharak, S., Wan, D. C., Longaker, M. T. LIPPINCOTT WILLIAMS & WILKINS. 2022: S196
  • Where There Is Fat There Is Fibrosis: Elucidating the Mechanisms of Creeping Fat-Driven Stricture Formation Bauer-Rowe, K. E., Kim, A., Griffin, M., Foster, D., Guardino, N., Guo, J. L., Talbott, H. E., Norton, J. A., Hyun, J. S., Longaker, M. T. LIPPINCOTT WILLIAMS & WILKINS. 2022: S59-S60
  • Multiomic analysis reveals conservation of cancer-associated fibroblast phenotypes across species and tissue of origin. Cancer cell Foster, D. S., Januszyk, M., Delitto, D., Yost, K. E., Griffin, M., Guo, J., Guardino, N., Delitto, A. E., Chinta, M., Burcham, A. R., Nguyen, A. T., Bauer-Rowe, K. E., Titan, A. L., Salhotra, A., Jones, R. E., da Silva, O., Lindsay, H. G., Berry, C. E., Chen, K., Henn, D., Mascharak, S., Talbott, H. E., Kim, A., Nosrati, F., Sivaraj, D., Ransom, R. C., Matthews, M., Khan, A., Wagh, D., Coller, J., Gurtner, G. C., Wan, D. C., Wapnir, I. L., Chang, H. Y., Norton, J. A., Longaker, M. T. 2022

    Abstract

    Cancer-associated fibroblasts (CAFs) are integral to the solid tumor microenvironment. CAFs were once thought to be a relatively uniform population of matrix-producing cells, but single-cell RNA sequencing has revealed diverse CAF phenotypes. Here, we further probed CAF heterogeneity with a comprehensive multiomics approach. Using paired, same-cell chromatin accessibility and transcriptome analysis, we provided an integrated analysis of CAF subpopulations over a complex spatial transcriptomic and proteomic landscape to identify three superclusters: steady state-like (SSL), mechanoresponsive (MR), and immunomodulatory (IM) CAFs. These superclusters are recapitulated across multiple tissue types and species. Selective disruption of underlying mechanical force or immune checkpoint inhibition therapy results in shifts in CAF subpopulation distributions and affected tumor growth. As such, the balance among CAF superclusters may have considerable translational implications. Collectively, this research expands our understanding of CAF biology, identifying regulatory pathways in CAF differentiation and elucidating therapeutic targets in a species- and tumor-agnostic manner.

    View details for DOI 10.1016/j.ccell.2022.09.015

    View details for PubMedID 36270275

  • Wound healing, fibroblast heterogeneity, and fibrosis. Cell stem cell Talbott, H. E., Mascharak, S., Griffin, M., Wan, D. C., Longaker, M. T. 2022; 29 (8): 1161-1180

    Abstract

    Fibroblasts are highly dynamic cells that play a central role in tissue repair and fibrosis. However, the mechanisms by which they contribute to both physiologic and pathologic states of extracellular matrix deposition and remodeling are just starting to be understood. In this review article, we discuss the current state of knowledge in fibroblast biology and heterogeneity, with a primary focus on the role of fibroblasts in skin wound repair. We also consider emerging techniques in the field, which enable an increasingly nuanced and contextualized understanding of these complex systems, and evaluate limitations of existing methodologies and knowledge. Collectively, this review spotlights a diverse body of research examining an often-overlooked cell type-the fibroblast-and its critical functions in wound repair and beyond.

    View details for DOI 10.1016/j.stem.2022.07.006

    View details for PubMedID 35931028

  • Musculoskeletal tissue engineering: Adipose derived stromal cell implementation for the treatment of osteoarthritis. Biomaterials Tevlin, R., desJardins-Park, H., Huber, J., DiIorio, S. E., Longaker, M. T., Wan, D. C. 2022; 286: 121544

    Abstract

    Osteoarthritis (OA) is a progressive degenerative joint disease which results in chronic degeneration of articular cartilage and sclerosis of bone. While tendons and ligaments may heal to a limited extent, articular cartilage has poor intrinsic regenerative potential, and critical-sized bone defects and pathological fractures cannot regenerate spontaneously. OA represents a significant burden of disease globally, affecting 240 million people in the world. The objective of tissue engineering is to recapitulate the natural healing cascade and developmental process by transplanting stromal and progenitor cells which can act directly or indirectly. As the ultimate goal of regenerative medicine is to avoid in vitro expansion of cells and its associated complications, the adipose-derived stromal cell (ASC) is an attractive progenitor cell for tissue engineering for treatment of OA. While clinical studies are still in their infancy, ASCs together with novel scaffold materials represent promising treatment options for patients suffering from OA. How ASCs exert their regenerative potential is a topic of debate, whereby it may be a result of direct differentiation of ASCs into the desired regenerating tissue, and/or through paracrine activity. With the advancement of material science, it is increasingly possible to enhance engraftment of ASCs through the use of biomaterials or to direct progenitor cell fate by activating biophysical signals through designed material microstructures. There are currently over 180 completed or ongoing registered early stage clinical trials involving ASCs, with 17 completed studies reviewed herein detailing the use of ASCs in OA. In order for ASC therapy to become an "off-the-shelf" option for treating OA, several strategies are currently being explored such as ASC cryopreservation and use of allogeneic ASCs. Newer approaches, such as exosome therapy, allow for the use of acellular ASC-derived therapies and are also currently the focus of ongoing investigations.

    View details for DOI 10.1016/j.biomaterials.2022.121544

    View details for PubMedID 35633592

  • Adipocytes Transition To Pro-Fibrotic Fibroblasts And Contribute To Muscle Fibrosis Following Nerve Injury Spielman, A. F., Griffin, M., Guardino, N., desJardins-Park, H. E., Bauer-Rowe, K. E., Guo, J. L., Parker, J., Abbas, D. B., Wan, D., Longaker, M. T. WILEY. 2022: A3-A4
  • Multi-omic analysis reveals divergent molecular events in scarring and regenerative wound healing. Cell stem cell Mascharak, S., Talbott, H. E., Januszyk, M., Griffin, M., Chen, K., Davitt, M. F., Demeter, J., Henn, D., Bonham, C. A., Foster, D. S., Mooney, N., Cheng, R., Jackson, P. K., Wan, D. C., Gurtner, G. C., Longaker, M. T. 1800

    Abstract

    Regeneration is the holy grail of tissue repair, but skin injury typically yields fibrotic, non-functional scars. Developing pro-regenerative therapies requires rigorous understanding of the molecular progression from injury to fibrosis or regeneration. Here, we report the divergent molecular events driving skin wound cells toward scarring or regenerative fates. We profile scarring versus YAP-inhibition-induced wound regeneration at the transcriptional (single-cell RNA sequencing), protein (timsTOF proteomics), and tissue (extracellular matrix ultrastructural analysis) levels. Using cell-surface barcoding, we integrate these data to reveal fibrotic and regenerative "molecular trajectories" of healing. We show that disrupting YAP mechanotransduction yields regenerative repair by fibroblasts with activated Trps1 and Wnt signaling. Finally, via invivo gene knockdown and overexpression in wounds, we identify Trps1 as a key regulatory gene that is necessary and partially sufficient for wound regeneration. Our findings serve as a multi-omic map of wound regeneration and could have therapeutic implications for pathologic fibroses.

    View details for DOI 10.1016/j.stem.2021.12.011

    View details for PubMedID 35077667

  • Where There Is Fat There Is Fibrosis: Elucidating the Mechanisms of Creeping Fat-Driven Stricture Formation Bauer-Rowe, K. E., Griffin, M., Foster, D., desJardins-Park, H. E., Mascharak, S., Norton, J. A., Hyun, J. S., Longaker, M. T. ELSEVIER SCIENCE INC. 2021: S65
  • From Chronic Wounds to Scarring: The Growing Healthcare Burden of Under- and Over-healing Wounds. Advances in wound care desJardins-Park, H. E., Gurtner, G. C., Wan, D. C., Longaker, M. T. 2021

    Abstract

    SIGNIFICANCE: Wound healing is the largest medical market without an existing small molecule/drug treatment. Both "under-healing" (chronic wounds) and "over-healing" (scarring) cause a substantial biomedical burden and lifelong consequences for patients. These problems cost tens of billions of dollars per year in the United States alone, a number expected to grow as the population ages and the prevalence of common comorbidities (e.g., diabetes) rises. However, no therapies currently exist to produce the "ideal" healing outcome: efficient wound repair via regeneration of normal tissue. Recent Advances: Ongoing research continues to illuminate possible therapeutic avenues for wound healing. By identifying underlying mechanisms of wound repair - for instance, tissue mechanics' role in fibrosis, or cell populations that modulate wound healing and scarring - novel molecular targets may be defined. This Advances in Wound Care Forum issue includes reviews of scientific literature and original research from the Hagey Laboratory for Pediatric Regenerative Medicine at Stanford and its alumni, including developing approaches for encouraging wound healing, minimizing fibrosis, and coaxing regeneration.CRITICAL ISSUES: Wound healing problems reflect an enormous and rapidly expanding clinical burden. The issues of both under- and over-healing wound outcomes will continue to expand as their underlying causes (e.g., diabetes) grow. Targeted treatments are needed to enable wound repair with functional tissue restoration and decreased scarring.FUTURE DIRECTIONS: Basic scientists will continue to refine understanding of factors driving undesirable wound outcomes. These discoveries are beginning to be translated and, in the coming years, will hopefully form the foundation for anti-scarring drugs and other wound therapeutics.

    View details for DOI 10.1089/wound.2021.0039

    View details for PubMedID 34521257

  • JUN promotes hypertrophic skin scarring via CD36 in preclinical in vitro and in vivo models. Science translational medicine Griffin, M. F., Borrelli, M. R., Garcia, J. T., Januszyk, M., King, M., Lerbs, T., Cui, L., Moore, A. L., Shen, A. H., Mascharak, S., Diaz Deleon, N. M., Adem, S., Taylor, W. L., desJardins-Park, H. E., Gastou, M., Patel, R. A., Duoto, B. A., Sokol, J., Wei, Y., Foster, D., Chen, K., Wan, D. C., Gurtner, G. C., Lorenz, H. P., Chang, H. Y., Wernig, G., Longaker, M. T. 2021; 13 (609): eabb3312

    Abstract

    [Figure: see text].

    View details for DOI 10.1126/scitranslmed.abb3312

    View details for PubMedID 34516825

  • Modulating cellular responses to mechanical forces to promote wound regeneration. Advances in wound care Mascharak, S., desJardins-Park, H. E., Davitt, M. F., Guardino, N. J., Gurtner, G. C., Wan, D. C., Longaker, M. T. 2021

    Abstract

    SIGNIFICANCE: Skin scarring poses a major biomedical burden for hundreds of millions of patients annually. However, this burden could be mitigated by therapies that promote wound regeneration, with full recovery of skin's normal adnexa, matrix ultrastructure, and mechanical strength. Recent Advances: The observation of wound regeneration in several mouse models suggests a retained capacity for postnatal mammalian skin to regenerate under the right conditions. Mechanical forces are a major contributor to skin fibrosis and a prime target for devices and therapeutics that could promote skin regeneration.CRITICAL ISSUES: Wound induced hair neogenesis, Acomys "spiny" mice, Murphy Roths Large (MRL) mice, and mice treated with mechanotransduction inhibitors all show various degrees of wound regeneration. Comparison of regenerating wounds in these models against scarring wounds reveals differences in ECM interactions and in mechanosensitive activation of key signaling pathways, including Wnt, Sonic hedgehog, Focal Adhesion Kinase, and Yes-associated protein. The advent of single cell "omics" technologies has deepened this understanding and revealed that regeneration may recapitulate development in certain contexts, though it is unknown whether these mechanisms are relevant to healing in tight-skinned animals such as humans.FUTURE DIRECTIONS: While early findings in mice are promising, comparison across model systems is needed to resolve conflicting mechanisms and to identify conserved master regulators of skin regeneration. There also remains a dire need for studies on mechanomodulation of wounds in large, tight-skinned animals such as red Duroc pigs, which better approximate human wound healing.

    View details for DOI 10.1089/wound.2021.0040

    View details for PubMedID 34465219

  • Leveraging Mechanical Forces to Target Insulin Injection-Induced Lipohypertrophy and Fibrosis. Diabetes spectrum : a publication of the American Diabetes Association desJardins-Park, H. E., Wan, D. C. 2021; 34 (3): 308-312

    View details for DOI 10.2337/ds20-0048

    View details for PubMedID 34511858

  • Optimizing Treatment of Hand Infections: Is MRSA Coverage Always Necessary? Plastic and reconstructive surgery. Global open Oliver, J. D., Pridgen, B. C., desJardins-Park, H. E., Curtin, C., Fox, P. M. 2021; 9 (6): e3619

    Abstract

    Multiple publications have highlighted the prevalence of methicillin resistant Staphylococcus aureus (MRSA) as a cause of hand infections. We hypothesized that these publications have shifted the empiric treatment of hand infections. The aim of this study was to identify the current standard of care, the most common causative bacteria, and factors leading to extended length of stay for hand infection patients at a suburban hospital to improve treatment and establish an optimized care protocol.Methods: Retrospective cohort analysis was conducted to identify all patients admitted for hand infections over an 8-year period. A comprehensive chart review of each patient's hospital course was completed.Results: A total of 70 patients were included. Maximum white blood cell count ≥ 12 was associated with a significantly longer hospital length of stay (9.1 days versus 5.4 days) compared to WBC values < 12 (P < 0.05). Also, 11 out of 23 (47.8%) underwent two or more incision and drainages (I&D's), compared with patients with maximum WBC < 12. Vancomycin use as an empiric antibiotic was widespread (68 patients, 97.1%), despite only 14 (20%) having MRSA positive cultures. Univariate analysis identified a significant increased likelihood for increased length of stay (P < 0.05) and rise in creatinine (P < 0.05) in patients with an initial vancomycin trough level > 20.Conclusions: This analysis of hand infection treatment in a suburban hospital demonstrates the incidence of MRSA hand infections may not be universally high across institutions. Each hospital should review its own data to optimize hand infection treatment and its associated costs.

    View details for DOI 10.1097/GOX.0000000000003619

    View details for PubMedID 34150420

  • Wnt-active Engrailed-1 Lineage-negative Fibroblasts Mediate Postnatal Skin Regeneration Mascharak, S., desJardins-Park, H. E., Januszyk, M., Chen, K., Davitt, M. F., Demeter, J., Henn, D., Griffin, M., Bonham, C. A., Mooney, N., Cheng, R., Jackson, P. K., Wan, D. C., Gurtner, G. C., Longaker, M. T. WILEY. 2021: A30
  • Single Cell RNA Sequencing Reveals Fibroblast Heterogeneity Across Embryonic Origins Of Skin Griffin, M., King, M., Chen, K., desJardins-Park, H., Mascharak, S., Fahy, E., Guardino, N., Lavin, C., Abbas, D., Januszyk, M., Wan, D., Longaker, M. WILEY. 2021: A11-A12
  • Novel Genetic Analysis Of MRL Mice Reveals That Complement Inhibition By Factor H Reduces Scarring desJardins-Park, H. E., Mack, K. L., Guardino, N., Griffin, M., Davitt, M. F., Mascharak, S., Wan, D. C., Fraser, H. B., Longaker, M. T. WILEY. 2021: A13
  • Adipocytes In Dermal Wounds Undergo Conversion To Pro-fibrotic Fibroblasts That Contribute To Scar Formation Guardino, N., desJardins-Park, H. E., Griffin, M., Bauer-Rowe, K. E., King, M. E., King, M. E., Mascharak, S., Longaker, M. T. WILEY. 2021: A31
  • Transgenic Inhibition Of Engrailed-1 Results In Endogenous Postnatal Skin Regeneration Mascharak, S., desJardins-Park, H. E., Davitt, M. F., Chen, K., Griffin, M., Guardino, N., Lorenz, H., Wan, D. C., Gurtner, G. C., Longaker, M. T. WILEY. 2021: A14-A15
  • Preventing Engrailed-1 activation in fibroblasts yields wound regeneration without scarring. Science (New York, N.Y.) Mascharak, S., desJardins-Park, H. E., Davitt, M. F., Griffin, M., Borrelli, M. R., Moore, A. L., Chen, K., Duoto, B., Chinta, M., Foster, D. S., Shen, A. H., Januszyk, M., Kwon, S. H., Wernig, G., Wan, D. C., Lorenz, H. P., Gurtner, G. C., Longaker, M. T. 2021; 372 (6540)

    Abstract

    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).

    View details for DOI 10.1126/science.aba2374

    View details for PubMedID 33888614

  • Discussion: Overcoming the Patent Gap: A Guide to Patenting for Plastic Surgeons. Plastic and reconstructive surgery Januszyk, M., desJardins-Park, H. E., Gurtner, G. C., Longaker, M. T. 2021; 148 (4): 918-919

    View details for DOI 10.1097/PRS.0000000000008394

    View details for PubMedID 34550949

  • Endogenous Mechanisms of Craniomaxillofacial Repair: Toward Novel Regenerative Therapies. Frontiers in oral health desJardins-Park, H. E., Mascharak, S., Longaker, M. T., Wan, D. C. 1800; 2: 676258

    Abstract

    In the fields of oral and craniomaxillofacial surgery, regeneration of multiple tissue types-including bone, skin, teeth, and mucosal soft tissue-is often a desired outcome. However, limited endogenous capacity for regeneration, as well as predisposition of many tissues to fibrotic healing, may prevent recovery of normal form and function for patients. Recent basic science research has advanced our understanding of molecular and cellular pathways of repair in the oral/craniofacial region and how these are influenced by local microenvironment and embryonic origin. Here, we review the current state of knowledge in oral and craniomaxillofacial tissue repair/regeneration in four key areas: bone (in the context of calvarial defects and mandibular regeneration during distraction osteogenesis); skin (in the context of cleft lip/palate surgery); oral mucosa (in the context of minimally scarring repair of mucosal injuries); and teeth (in the context of dental disease/decay). These represent four distinct healing processes and outcomes. We will discuss both divergent and conserved pathways of repair in these contexts, with an eye toward fundamental mechanisms of regeneration vs. fibrosis as well as translational research directions. Ultimately, this knowledge can be leveraged to develop new cell-based and molecular treatment strategies to encourage bone and soft tissue regeneration in oral and craniomaxillofacial surgery.

    View details for DOI 10.3389/froh.2021.676258

    View details for PubMedID 35048022

  • Prrx1 Fibroblasts Represent a Pro-fibrotic Lineage in the Mouse Ventral Dermis. Cell reports Leavitt, T., Hu, M. S., Borrelli, M. R., Januszyk, M., Garcia, J. T., Ransom, R. C., Mascharak, S., desJardins-Park, H. E., Litzenburger, U. M., Walmsley, G. G., Marshall, C. D., Moore, A. L., Duoto, B., Adem, S., Foster, D. S., Salhotra, A., Shen, A. H., Griffin, M., Shen, E. Z., Barnes, L. A., Zielins, E. R., Maan, Z. N., Wei, Y., Chan, C. K., Wan, D. C., Lorenz, H. P., Chang, H. Y., Gurtner, G. C., Longaker, M. T. 2020; 33 (6): 108356

    Abstract

    Fibroblast heterogeneity has been shown within the unwounded mouse dorsal dermis, with fibroblast subpopulations being identified according to anatomical location and embryonic lineage. Using lineage tracing, we demonstrate that paired related homeobox 1 (Prrx1)-expressing fibroblasts are responsible for acute and chronic fibroses in the ventral dermis. Single-cell transcriptomics further corroborated the inherent fibrotic characteristics of Prrx1 fibroblasts during wound repair. In summary, we identify and characterize a fibroblast subpopulation in the mouse ventral dermis with intrinsic scar-forming potential.

    View details for DOI 10.1016/j.celrep.2020.108356

    View details for PubMedID 33176144

  • A Surgical Model for Investigating the Role of Creeping Fat in Intestinal Fibrosis Bauer-Rowe, K. E., Foster, D., Titan, A., Chinta, M., desJardins-Park, H., Griffin, M., Longaker, M. T. ELSEVIER SCIENCE INC. 2020: S50–S51
  • Elucidating Molecular Drivers of Wound Regeneration in MRL Mice Via Novel Transcriptomic Analyses desJardins-Park, H. E., Mack, K. L., Davitt, M. F., Griffin, M., Mascharak, S., Fraser, H. B., Longaker, M. T. ELSEVIER SCIENCE INC. 2020: S225
  • Peripheral Motor Neuron Activity Influences over Local Sarcoma Progression Davitt, M., Foster, D., Mascharak, S., desJardins-Park, H., Norton, J., Longaker, M. T. ELSEVIER SCIENCE INC. 2020: S230–S231
  • Detection, Scoring, and Classification of Solid Organ Fibroses with Machine Learning Analysis Mascharak, S., desJardins-Park, H. E., Davitt, M., Foster, D. S., Chinta, M., Wan, D. C., Wernig, G., Longaker, M. T. ELSEVIER SCIENCE INC. 2020: S222
  • Fibroblast Heterogeneity in Wound Healing: Hurdles to Clinical Translation. Trends in molecular medicine Mascharak, S., desJardins-Park, H. E., Longaker, M. T. 2020

    Abstract

    Recent work has revealed that fibroblasts are remarkably heterogeneous cells, but the appropriate lens through which to study this variation (lineage, phenotype, and plasticity) and its relevance to human biology remain unclear. In this opinion article, we comment on recent breakthroughs in our understanding of fibroblast heterogeneity during skin wound healing, and on open questions that must be addressed to clinically translate these findings in order to minimize scarring in patients. We emphasize the need for experimental models of wound healing that better approximate human biology, as well as comparison of scarring and regenerative phenotypes to uncover master regulators of fibrosis.

    View details for DOI 10.1016/j.molmed.2020.07.008

    View details for PubMedID 32800679

  • Rewriting the Future: Promises and Limits of Germline Gene Editing in Craniofacial Surgery. The Journal of craniofacial surgery Davitt, M., Mascharak, S., desJardins-Park, H., Chinta, M., Wan, D. C., Longaker, M. T. 2020

    View details for DOI 10.1097/SCS.0000000000006602

    View details for PubMedID 32796298

  • Harnessing novel gene expression analyses to identify drivers of regenerative ear wound healing in MRL mice desJardins-Park, H. E., Mack, K. L., Davitt, M. F., Griffin, M., Fraser, H. B., Longaker, M. T. WILEY. 2020: S25
  • Doxycycline Reduces Scar Thickness and Improves Collagen Architecture ANNALS OF SURGERY Moore, A. L., desJardins-Park, H. E., Duoto, B. A., Mascharak, S., Murphy, M. P., Irizarry, D. M., Foster, D. S., Jones, R. E., Barnes, L. A., Marshall, C. D., Ransom, R. C., Wernig, G., Longaker, M. T. 2020; 272 (1): 183–93
  • Fibroblast Heterogeneity in and Its Implications for Plastic and Reconstructive Surgery: A Basic Science Review PLASTIC AND RECONSTRUCTIVE SURGERY-GLOBAL OPEN desJardins-Park, H. E., Chinta, M. S., Foster, D. S., Borrelli, M. R., Shen, A. H., Wan, D. C., Longaker, M. T. 2020; 8 (6)
  • Fibroblast Heterogeneity in and Its Implications for Plastic and Reconstructive Surgery: A Basic Science Review. Plastic and reconstructive surgery. Global open desJardins-Park, H. E., Chinta, M. S., Foster, D. S., Borrelli, M. R., Shen, A. H., Wan, D. C., Longaker, M. T. 2020; 8 (6): e2927

    Abstract

    Fibroblasts' integral role in tissue development, maintenance, and disease represents a fast-growing field of basic science research. Although fibroblasts were long thought to be a homogeneous cell population, recent research has illuminated the unforeseen complexity of these cells, giving rise to the rapidly expanding research field of "fibroblast heterogeneity." Fibroblasts play a critical role in states of tissue fibrosis such as skin scarring, which affects hundreds of millions of patients annually and causes severe aesthetic, developmental, and functional morbidity. Beyond scarring, major organ fibrosis is an enormous public health concern responsible for nearly half of all deaths in the United States. Because fibrosis is a conserved response to tissue damage in all organs, the study of fibroblasts throughout the body may help us to understand their role in the conditions most relevant to plastic and reconstructive surgery-for instance, skin scarring (eg, from burns, traumatic lacerations, or surgical incisions), "pathological" scarring (hypertrophic scars, keloids), and capsular contracture. Here, we present a basic science review of fibroblast heterogeneity in wound healing, cancer, organ fibrosis, and human dermal architecture. The field of fibroblast heterogeneity is young, and many of the insights discussed have yet to be translated clinically. However, plastic surgeons stand in a unique position to bridge these discoveries into clinical realities. We hope this information can spur readers to consider both what questions in plastic surgery can be studied from the lens of fibroblast heterogeneity, and how these preclinical insights can be translated to improving care of our patients.

    View details for DOI 10.1097/GOX.0000000000002927

    View details for PubMedID 32766071

    View details for PubMedCentralID PMC7339369

  • "Tissues in a Dish": A Review of Organoids in Plastic Surgery. Plastic and reconstructive surgery. Global open Chinta, M. S., desJardins-Park, H. E., Wan, D. C., Longaker, M. T. 2020; 8 (4): e2787

    Abstract

    Organoids are in vitro miniaturized organ models-or, colloquially, "organs in a dish." These 3-dimensional, multicellular structures are classically derived from pluripotent or multipotent stem cells. When guided by tissue-specific molecular factors, these cells exhibit self-organizing abilities that allow them to accurately recapitulate the architecture and function of the organ of interest. Organoid technology is a rapidly expanding field that endows researchers with an unprecedented ability to recreate, study, and manipulate complex biologic processes in vitro. When compared with standard 2- and 3-dimensional culture systems, which rely on co-culturing pre-established cell types, organoids provide a more biomimetic model with which to study the intercellular interactions necessary for in vivo organ function and architecture. Organoids have the potential to impact all avenues of medicine, including those fields most relevant to plastic and reconstructive surgery such as wound healing, oncology, craniofacial reconstruction, and burn care. In addition to their ability to serve as a novel tool for studying human-specific disease, organoids may be used for tissue engineering with the goal of developing biomimetic soft-tissue substitutes, which would be especially valuable to the plastic surgeon. Although organoids hold great promise for the field of plastic surgery, technical challenges in creating vascularized, multilineage organoids must be overcome to allow for the integration of this technology in clinical practice. This review provides a brief history of the organoid, highlights its potential clinical applications, discusses certain limitations, and examines the impact that this technology may have on the field of plastic and reconstructive surgery.

    View details for DOI 10.1097/GOX.0000000000002787

    View details for PubMedID 32440447

    View details for PubMedCentralID PMC7209840

  • Understanding the impact of fibroblast heterogeneity on skin fibrosis. Disease models & mechanisms Griffin, M. F., desJardins-Park, H. E., Mascharak, S. n., Borrelli, M. R., Longaker, M. T. 2020; 13 (6)

    Abstract

    Tissue fibrosis is the deposition of excessive extracellular matrix and can occur as part of the body's natural wound healing process upon injury, or as a consequence of diseases such as systemic sclerosis. Skin fibrosis contributes to significant morbidity due to the prevalence of injuries resulting from trauma and burn. Fibroblasts, the principal cells of the dermis, synthesize extracellular matrix to maintain the skin during homeostasis and also play a pivotal role in all stages of wound healing. Although it was previously believed that fibroblasts are homogeneous and mostly quiescent cells, it has become increasingly recognized that numerous fibroblast subtypes with unique functions and morphologies exist. This Review provides an overview of fibroblast heterogeneity in the mammalian dermis. We explain how fibroblast identity relates to their developmental origin, anatomical site and precise location within the skin tissue architecture in both human and mouse dermis. We discuss current evidence for the varied functionality of fibroblasts within the dermis and the relationships between fibroblast subtypes, and explain the current understanding of how fibroblast subpopulations may be controlled through transcriptional regulatory networks and paracrine communications. We consider how fibroblast heterogeneity can influence wound healing and fibrosis, and how insight into fibroblast heterogeneity could lead to novel therapeutic developments and targets for skin fibrosis. Finally, we contemplate how future studies should be shaped to implement knowledge of fibroblast heterogeneity into clinical practice in order to lessen the burden of skin fibrosis.

    View details for DOI 10.1242/dmm.044164

    View details for PubMedID 32541065

  • Intrinsic Chromatin State and Extrinsic Wound-Related Cues Can Coordinate to Activate Fibroblasts for Scarring desJardins-Park, H. E., Moore, A. L., Litzenburger, U., Mascharak, S., Chinta, M., Ransom, R. C., Hu, M. S., Lorenz, H. P., Chang, H. Y., Longaker, M. T. ELSEVIER SCIENCE INC. 2019: S223–S224
  • Regenerative Skin Healing Through Targeted Modulation of Engrailed1-Negative Fibroblasts Mascharak, S., desJardins-Park, H. E., Moore, A. L., Borrelli, M. R., Chinta, M., Foster, D., Lorenz, H., Longaker, M. T. ELSEVIER SCIENCE INC. 2019: S228
  • The Spectrum of Scarring in Craniofacial Wound Repair. Frontiers in physiology desJardins-Park, H. E., Mascharak, S., Chinta, M. S., Wan, D. C., Longaker, M. T. 2019; 10: 322

    Abstract

    Fibrosis is intimately linked to wound healing and is one of the largest causes of wound-related morbidity. While scar formation is the normal and inevitable outcome of adult mammalian cutaneous wound healing, scarring varies widely between different anatomical sites. The spectrum of craniofacial wound healing spans a particularly diverse range of outcomes. While most craniofacial wounds heal by scarring, which can be functionally and aesthetically devastating, healing of the oral mucosa represents a rare example of nearly scarless postnatal healing in humans. In this review, we describe the typical wound healing process in both skin and the oral cavity. We present clinical correlates and current therapies and discuss the current state of research into mechanisms of scarless healing, toward the ultimate goal of achieving scarless adult skin healing.

    View details for DOI 10.3389/fphys.2019.00322

    View details for PubMedID 30984020

    View details for PubMedCentralID PMC6450464

  • Quality of Randomized Controlled Trials for Surgical Treatment of Carpal Tunnel Syndrome: A Systematic Review. Plastic and reconstructive surgery Long, C., Azad, A. D., desJardins-Park, H. E., Fox, P. M. 2019; 143 (3): 791–99

    Abstract

    BACKGROUND: Randomized controlled trials are considered the gold standard in evidence-based medicine. The authors conducted a systematic review to evaluate the quantity, quality, and trends of randomized controlled trials that assess surgical treatment of carpal tunnel syndrome.METHODS: The authors identified randomized controlled trials comparing two or more surgical interventions for carpal tunnel syndrome in PubMed, Cochrane, Scopus, Google Scholar, and Clinicaltrials.gov. Two independent reviewers evaluated articles for inclusion, extracted data, and assessed randomized controlled trial quality using the Jadad score.RESULTS: Of 2253 identified studies, 58 met full inclusion criteria. They were published between 1985 and 2015, with a significant increase over time (p = 0.003). They were most frequently published in Journal of Hand Surgery (European Volume) [n = 15 (25.9 percent)]. Most randomized controlled trials were single-center studies [n = 54 (93.1 percent)] conducted in the United Kingdom [n = 13 (22.4 percent)] or the United States [n = 10 (17.2 percent)], with a mean study size of 80.1 ± 55.5 patients. Funding source was unknown in 62.1 percent (n = 36). Three-quarters [n = 44 (75.9 percent)] of randomized controlled trials did not define the primary outcome measure(s). Less than 30 percent (n = 17) of randomized controlled trials conducted a power analysis. Only four studies with patients reported lost to follow-up provided an explanation for each patient. Six randomized controlled trials (10.3 percent) conducted intention-to-treat analysis. The mean Jadad score was 2.14 ± 1.26, with no significant improvement over time (p = 0.245).CONCLUSIONS: Despite the significant increase in the number of randomized controlled trials published studying surgical treatment of carpal tunnel syndrome over time, a mean Jadad score of 2.14 with no change over time indicates a need for improvement in quality. Proper study design is key to avoiding introduction of bias and ensuring the validity of conclusions drawn.

    View details for PubMedID 30822284

  • Quality of Randomized Controlled Trials for Surgical Treatment of Carpal Tunnel Syndrome: A Systematic Review PLASTIC AND RECONSTRUCTIVE SURGERY Long, C., Azad, A. D., desJardins-Park, H. E., Fox, P. M. 2019; 143 (3): 791-799
  • Doxycycline Reduces Scar Thickness and Improves Collagen Architecture. Annals of surgery Moore, A. L., desJardins-Park, H. E., Duoto, B. A., Mascharak, S., Murphy, M. P., Irizarry, D. M., Foster, D. S., Jones, R. E., Barnes, L. A., Marshall, C. D., Ransom, R. C., Wernig, G., Longaker, M. T. 2018

    Abstract

    OBJECTIVE: To investigate the effects of local doxycycline administration on skin scarring.BACKGROUND: Skin scarring represents a major source of morbidity for surgical patients. Doxycycline, a tetracycline antibiotic with off-target effects on the extracellular matrix, has demonstrated antifibrotic effects in multiple organs. However, doxycycline's potential effects on skin scarring have not been explored in vivo.METHODS: Female C57BL/6J mice underwent dorsal wounding following an established splinted excisional skin wounding model. Doxycycline was administered by local injection into the wound base following injury. Wounds were harvested upon complete wound closure (postoperative day 15) for histological examination and biomechanical testing of scar tissue.RESULTS: A one-time dose of 3.90 mM doxycycline (2 mg/mL) within 12 hours of injury was found to significantly reduce scar thickness by 24.8% (P < 0.0001) without compromising tensile strength. The same effect could not be achieved by oral dosing. In doxycycline-treated scar matrices, collagen I content was significantly reduced (P = 0.0317) and fibers were favorably arranged with significantly increased fiber randomness (P = 0.0115). Common culprits of altered wound healing mechanics, including angiogenesis and inflammation, were not impacted by doxycycline treatment. However, engrailed1 profibrotic fibroblasts, responsible for scar extracellular matrix deposition, were significantly reduced with doxycycline treatment (P = 0.0005).CONCLUSIONS: Due to the substantial improvement in skin scarring and well-established clinical safety profile, locally administered doxycycline represents a promising vulnerary agent. As such, we favor rapid translation to human patients as an antiscarring therapy.

    View details for PubMedID 30585822

  • Quality of surgical randomized controlled trials in hand surgery: a systematic review JOURNAL OF HAND SURGERY-EUROPEAN VOLUME Long, C., desJardins-Park, H. E., Popat, R., Fox, P. M. 2018; 43 (8): 801-807
  • Fibroblasts and wound healing: an update. Regenerative medicine des Jardins-Park, H. E., Foster, D. S., Longaker, M. T. 2018

    View details for PubMedID 30062921

  • Fibroblasts and wound healing: an update REGENERATIVE MEDICINE desJardins-Park, H. E., Foster, D. S., Longaker, M. T. 2018; 13 (5): 491–95
  • Quality of surgical randomized controlled trials in hand surgery: a systematic review. The Journal of hand surgery, European volume Long, C., desJardins-Park, H. E., Popat, R., Fox, P. M. 2018: 1753193418780184

    Abstract

    We assessed the quantity, quality and trends of randomized controlled trials comparing hand surgical interventions. Study characteristics were collected for 125 randomized controlled trials comparing hand surgical interventions. The Jadad scale (0-5), which assesses methodological quality of trials, was calculated. Logistic regressions were conducted to determine associations with the Jadad score. The studies were published between 1981 and 2015, with an increase over time, most often in Journal of Hand Surgery (European). Mean study size was 68 patients. Mean Jadad score was 2.1, without improvement over time. Thirty percent conducted a power analysis and 8% an intention-to-treat analysis. Studies conducted in the United Kingdom and with smaller sample sizes, power analysis and intention-to-treat analysis were associated with a higher Jadad score. The quantity of trials has increased over time while methodological quality has remained low, indicating a need to improve quality of trials in hand surgery literature.

    View details for PubMedID 29896997