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28


Dermal β-Catenin Is Required for Hedgehog-Driven Hair Follicle Neogenesis

Lim, Chae Ho; Kaminaka, Annette; Lee, Soung-Hoon; Moore, Simone; Cronstein, Bruce N; Rabbani, Piul S; Ito, Mayumi
Hair follicle neogenesis (HFN) occurs following large skin excisions in mice, serving as a rare regenerative model in mammalian wound healing. Wound healing typically results in fibrosis in mice and humans. We previously showed small skin excisions in mice result in scarring devoid of HFN, displaying features of non-regenerative healing, and Hedgehog (Hh) activation in the dermis of such wounds can induce HFN. In this study, we sought to verify the role of dermal Wnt/β-catenin signaling in HFN, as this pathway is essential for HF development, but is also paradoxically well-characterized in fibrosis of adult wounds. By deletion of β-catenin in large wound myofibroblasts, we show Wnt/β-catenin signaling is required for endogenous mechanisms of HFN. Through utilizing a combined mouse model that simultaneously induces deletion of β-catenin and constitutive activation of Smoothened (Smo) in myofibroblasts, we also found β-catenin is required for Hh-driven DP formation. Transcriptome analysis confirms Wnt/β-catenin and Hh pathways are activated in dermal papilla (DP) cells. Our results indicate that Wnt-active fibrotic status may also create a permissive state for the regenerative function of Hh, suggesting that activation of both Wnt and Hh pathways in skin wound fibroblasts must be ensured in future strategies to promote HFN.
PMID: 38810955
ISSN: 1523-1747
CID: 5663682

Molecular Signature Associated With Acute Rejection in Vascularized Composite Allotransplantation

Cassidy, Michael F; Doudican, Nicole A; Frazzette, Nicholas; Rabbani, Piul S; Carucci, John A; Gelb, Bruce E; Rodriguez, Eduardo D; Lu, Catherine P; Ceradini, Daniel J
BACKGROUND/UNASSIGNED:A deeper understanding of acute rejection in vascularized composite allotransplantation is paramount for expanding its utility and longevity. There remains a need to develop more precise and accurate tools for diagnosis and prognosis of these allografts, as well as alternatives to traditional immunosuppressive regimens. METHODS/UNASSIGNED:Twenty-seven skin biopsies collected from 3 vascularized composite allotransplantation recipients, consisting of face and hand transplants, were evaluated by histology, immunohistochemistry staining, and gene expression profiling. RESULTS/UNASSIGNED:significantly predicted inflammation specific to vascularized composite allografts that required therapeutic intervention. CONCLUSIONS/UNASSIGNED:The mechanism of vascularized composite allograft-specific inflammation and rejection appears to be conserved across different patients and skin on different anatomical sites. A concise gene signature can be utilized to ascertain graft status along with a continuous scale, providing valuable diagnostic and prognostic information to supplement current gold standards of graft evaluation.
PMCID:11415116
PMID: 39310283
ISSN: 2373-8731
CID: 5802822

Exosome Loaded Protein Hydrogel for Enhanced Gelation Kinetics and Wound Healing

Britton, Dustin; Almanzar, Dianny; Xiao, Yingxin; Shih, Hao-Wei; Legocki, Jakub; Rabbani, Piul; Montclare, Jin Kim
Exosomes are being increasingly explored in biomedical research for wound healing applications. Exosomes can improve blood circulation and endocrine signaling, resulting in enhanced cell regeneration. However, exosome treatments suffer from low retention and bioavailability of exosomes at the wound site. Hydrogels are a popular tool for drug delivery due to their ability to encapsulate drugs in their network and allow for targeted release. Recently, hydrogels have proven to be an effective method to provide increased rates of wound healing when combined with exosomes that can be applied noninvasively. We have designed a series of single-domain protein-based hydrogels capable of physical cross-linking and upper critical solution temperature (UCST) behavior. Hydrogel variant Q5, previously designed with improved UCST behavior and a significantly enhanced gelation rate, is selected as a candidate for encapsulation release of exosomes dubbed Q5Exo. Q5Exo exhibits low critical gelation times and significant decreases in wound healing times in a diabetic mouse wound model showing promise as an exosome-based drug delivery tool and for future hybrid, noninvasive protein-exosome design.
PMID: 39173187
ISSN: 2576-6422
CID: 5680992

Minimally and Non-invasive Approaches to Rejection Identification in Vascularized Composite Allotransplantation

Stead, Thor S; Brydges, Hilliard T; Laspro, Matteo; Onuh, Ogechukwu C; Chaya, Bachar F; Rabbani, Piul S; Lu, Catherine P; Ceradini, Daniel J; Gelb, Bruce E; Rodriguez, Eduardo D
OBJECTIVE:Rejection is common and pernicious following Vascularized Composite Allotransplantation (VCA). Current monitoring and diagnostic modalities include the clinical exam which is subjective and biopsy with dermatohistopathologic Banff grading, which is subjective and invasive. We reviewed literature exploring non- and minimally invasive modalities for diagnosing and monitoring rejection (NIMMs) in VCA. METHODS:PubMed, Cochrane, and Embase databases were queried, 3125 unique articles were reviewed, yielding 26 included studies exploring 17 distinct NIMMs. Broadly, NIMMs involved Imaging, Liquid Biomarkers, Epidermal Sampling, Clinical Grading Scales, and Introduction of Additional Donor Tissue. RESULTS:Serum biomarkers including MMP3 and donor-derived microparticles rose with rejection onset. Epidermal sampling non-invasively enabled measurement of cytokine & gene expression profiles implicated in rejection. Both hold promise for monitoring. Clinical grading scales were useful diagnostically as was reflection confocal microscopy. Introducing additional donor tissue showed promise for preemptively identifying rejection but requires additional allograft tissue burden for the recipient. CONCLUSION/CONCLUSIONS:NIMMs have the potential to dramatically improve monitoring and diagnosis in VCA. Many modalities show promise however, additional research is needed and a multimodal algorithmic approach should be explored.
PMID: 37625211
ISSN: 1557-9816
CID: 5599092

Adenosine A2A receptor activation reduces chondrocyte senescence

Friedman, Benjamin; Larranaga-Vera, Ane; Castro, Cristina M; Corciulo, Carmen; Rabbani, Piul; Cronstein, Bruce N
Osteoarthritis (OA) pathogenesis is associated with reduced chondrocyte homeostasis and increased levels of cartilage cellular senescence. Chondrosenescence is the development of cartilage senescence that increases with aging joints and disrupts chondrocyte homeostasis and is associated with OA. Adenosine A2A receptor (A2AR) activation in cartilage via intra-articular injection of liposomal A2AR agonist, liposomal-CGS21680, leads to cartilage regeneration in vivo and chondrocyte homeostasis. A2AR knockout mice develop early OA isolated chondrocytes demonstrate upregulated expression of cellular senescence and aging-associated genes. Based on these observations, we hypothesized that A2AR activation would ameliorate cartilage senescence. We found that A2AR stimulation of chondrocytes reduced beta-galactosidase staining and regulated levels and cell localization of common senescence mediators p21 and p16 in vitro in the human TC28a2 chondrocyte cell line. In vivo analysis similarly showed A2AR activation reduced nuclear p21 and p16 in obesity-induced OA mice injected with liposomal-CGS21680 and increased nuclear p21 and p16 in A2AR knockout mouse chondrocytes compared to wild-type mice. A2AR agonism also increased activity of the chondrocyte Sirt1/AMPK energy-sensing pathway by enhancing nuclear Sirt1 localization and upregulating T172-phosphorylated (active) AMPK protein levels. Lastly, A2AR activation in TC28a2 and primary human chondrocytes reduced wild-type p53 and concomitantly increased p53 alternative splicing leading to increase in an anti-senescent p53 variant, Δ133p53α. The results reported here indicate that A2AR signaling promotes chondrocyte homeostasis in vitro and reduces OA cartilage development in vivo by reducing chondrocyte senescence.
PMID: 36884388
ISSN: 1530-6860
CID: 5448632

Evolution of a Plastic Surgery Summer Research Program: Lessons Learned from Programmatic Evaluation and Quality Enhancement

Alfonso, Allyson R.; Berman, Zoe P.; Diep, Gustave K.; Lee, Jasmine; Ramly, Elie P.; Diaz-Siso, J. Rodrigo; Rodriguez, Eduardo D.; Rabbani, Piul S.
Background: Early surgical exposure and research fellowships can influence medical students' specialty choice, increase academic productivity, and impact residency match. However, to our knowledge, there is no published guidance on the programmatic evaluation and quality enhancement necessary for the sustainability of formal plastic surgery summer research programs for first year medical students. We present seven years (2013-2020) of institutional experience in an effort to inform program development at other institutions. Methods: From 2013 to 2016, a sole basic science research arm existed. In 2017, a clinical research arm was introduced, with several supplemental activities, including surgical skills curriculum. A formalized selection process was instituted in 2014. Participant feedback was analyzed annually. Long-term outcomes included continued research commitment, productivity, and residency match. Results: The applicant pool reached 96 applicants in 2019, with 85% from outside institutions. Acceptance rate reached 7% in 2020. With adherence to a scoring rubric for applicant evaluation, good to excellent interrater reliability was achieved (intraclass correlation coefficient = 0.75). Long-term outcomes showed that on average per year, 28% of participants continued involvement in departmental research and 29% returned for dedicated research. Upon finishing medical school, participants had a mean of 7 ± 4 peer-reviewed publications. In total, 62% of participants matched into a surgical residency program, with 54% in integrated plastic surgery. Conclusions: A research program designed for first year medical students interested in plastic surgery can achieve academic goals. Students are provided with mentorship, networking opportunities, and tools for self-guided learning and career development.
SCOPUS:85148667224
ISSN: 2169-7574
CID: 5445782

Behind the scenes of extracellular vesicle therapy for skin injuries and disorders

Subhan, Bibi Sheleeza; Ki, Michelle; Verzella, Alexandra; Shankar, Shruthi; Rabbani, Piul
SIGNIFICANCE/CONCLUSIONS:Skin wounds and disorders compromise the protective functions of skin and patient quality of life. Though accessible on the surface, they are challenging to address due to paucity of effective therapies. Exogenous extracellular vesicles (EVs), cell-free derivatives of adult multipotent stromal cells (MSCs), are developing as a treatment modality. Knowledge of origin MSCs, EV processing and mode of action is necessary for directed use of EVs in preclinical studies and methodical translation. Recent advances: Nano to microscale EVs, though from non-skin cells, induce functional responses in cutaneous wound cellular milieu. EVs allow a shift from cell-based to cell-free/derived modalities by carrying the MSC beneficial factors but eliminating risks associated with MSC transplantation. EVs have demonstrated striking efficacy in resolution of preclinical wound models, specifically within the complexity of skin structure and wound pathology. CRITICAL ISSUES/RESULTS:To facilitate comparison across studies, tissue sources and processing of MSCs, culture conditions, isolation and preparations of EVs, and vesicle sizes require standardization as these criteria influence EV types and contents, and potentially determine the induced biological responses. Procedural parameters for all steps preceding the actual therapeutic administration may be the key to generating EVs that demonstrate consistent efficacy through known mechanisms. We provide a comprehensive review of such parameters and the subsequent tissue, cellular and molecular impact of the derived EVs in different skin wounds/disorders. FUTURE DIRECTIONS/CONCLUSIONS:We will gain more complete knowledge of EV-induced effects in skin, and specificity for different wounds/conditions. The safety and efficacy of current preclinical xenogenic applications will favor translation into allogenic clinical applications of EVs as a biologic.
PMID: 34806432
ISSN: 2162-1918
CID: 5063312

Profiling Gingivoperiosteoplasty (GPP): A Cross-Sectional Analysis Using a Nationally Validated Pediatric Surgery Database

Arias, Fernando D.; Rochlin, Danielle H.; Rabbani, Piul S.; Shetye, Pradip R.; Staffenberg, David A.; Flores, Roberto L.
Objective: Compare short term surgical outcomes and trends in cleft lip repair with or without gingivoperiosteoplasty (GPP). Design: Retrospective review of the ACS NSQIP-Pediatric database from 2014 to 2019. Patients: Patients between 2 and 18 months of age undergoing any initial cleft lip repair, with or without GPP, were selected via relevant CPT® codes. Main Outcome Measures: Patient demographics, comorbidities, 30-day readmissions and post-operative complications are assessed. Results: From 2014 to 2019, a total of 6269 patients were identified, of which 6.67% underwent GPP (n = 418). Patients undergoing GPP were significantly older with an average age of 9 months compared to 5 months in the non-GPP group (P <.001). Co-morbidities were similar amongst both cohorts, although patients undergoing GPP were more likely to have a higher ASA class (P =.006), cardiac risk factors (P =.012) and syndromic diagnosis (P <.001). There were no differences in 30-day short term surgical outcomes. GPP was associated with increased operative time by ~25 minutes when compared to cleft lip repair alone (P <.001). Conclusion: GPP was not associated with increased 30-day postoperative complications, readmission, reoperation, or total length of hospital stay, and was associated with an increased operative time of 25 minutes. Children undergoing GPP were significantly older in age and were more likely to have a higher ASA class/cardiac risk factors.
SCOPUS:85164556926
ISSN: 2732-5016
CID: 5550472

Bone Tissue Engineering Strategies for Alveolar Cleft: Review of Preclinical Results and Guidelines for Future Studies

Park, Jenn J; Rochlin, Danielle H; Parsaei, Yassmin; Shetye, Pradip R; Witek, Lukasz; Leucht, Philipp; Rabbani, Piul S; Flores, Roberto L
The current standard of care for an alveolar cleft defect is an autogenous bone graft, typically from the iliac crest. Given the limitations of alveolar bone graft surgery, such as limited supply, donor site morbidity, graft failure, and need for secondary surgery, there has been growing interest in regenerative medicine strategies to supplement and replace traditional alveolar bone grafts. Though there have been preliminary clinical studies investigating bone tissue engineering methods in human subjects, lack of consistent results as well as limitations in study design make it difficult to determine the efficacy of these interventions. As the field of bone tissue engineering is rapidly advancing, reconstructive surgeons should be aware of the preclinical studies informing these regenerative strategies. We review preclinical studies investigating bone tissue engineering strategies in large animal maxillary or mandibular defects and provide an overview of scaffolds, stem cells, and osteogenic agents applicable to tissue engineering of the alveolar cleft. An electronic search conducted in the PubMed database up to December 2021 resulted in 35 studies for inclusion in our review. Most studies showed increased bone growth with a tissue engineering construct compared to negative control. However, heterogeneity in the length of follow up, method of bone growth analysis, and inconsistent use of positive control groups make comparisons across studies difficult. Future studies should incorporate a pediatric study model specific to alveolar cleft with long-term follow up to fully characterize volumetric defect filling, cellular ingrowth, bone strength, tooth movement, and implant support.
PMID: 35678607
ISSN: 1545-1569
CID: 5248492

Small-molecule antagonism of the interaction of the RAGE cytoplasmic domain with DIAPH1 reduces diabetic complications in mice

Manigrasso, Michaele B; Rabbani, Piul; Egaña-Gorroño, Lander; Quadri, Nosirudeen; Frye, Laura; Zhou, Boyan; Reverdatto, Sergey; Ramirez, Lisa S; Dansereau, Stephen; Pan, Jinhong; Li, Huilin; D'Agati, Vivette D; Ramasamy, Ravichandran; DeVita, Robert J; Shekhtman, Alexander; Schmidt, Ann Marie
[Figure: see text].
PMID: 34818060
ISSN: 1946-6242
CID: 5063702