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Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1

Ceradini, Daniel J; Kulkarni, Anita R; Callaghan, Matthew J; Tepper, Oren M; Bastidas, Nicholas; Kleinman, Mark E; Capla, Jennifer M; Galiano, Robert D; Levine, Jamie P; Gurtner, Geoffrey C
The trafficking of circulating stem and progenitor cells to areas of tissue damage is poorly understood. The chemokine stromal cell-derived factor-1 (SDF-1 or CXCL12) mediates homing of stem cells to bone marrow by binding to CXCR4 on circulating cells. SDF-1 and CXCR4 are expressed in complementary patterns during embryonic organogenesis and guide primordial stem cells to sites of rapid vascular expansion. However, the regulation of SDF-1 and its physiological role in peripheral tissue repair remain incompletely understood. Here we show that SDF-1 gene expression is regulated by the transcription factor hypoxia-inducible factor-1 (HIF-1) in endothelial cells, resulting in selective in vivo expression of SDF-1 in ischemic tissue in direct proportion to reduced oxygen tension. HIF-1-induced SDF-1 expression increases the adhesion, migration and homing of circulating CXCR4-positive progenitor cells to ischemic tissue. Blockade of SDF-1 in ischemic tissue or CXCR4 on circulating cells prevents progenitor cell recruitment to sites of injury. Discrete regions of hypoxia in the bone marrow compartment also show increased SDF-1 expression and progenitor cell tropism. These data show that the recruitment of CXCR4-positive progenitor cells to regenerating tissues is mediated by hypoxic gradients via HIF-1-induced expression of SDF-1
PMID: 15235597
ISSN: 1078-8956
CID: 48194

Restoration of Nrf2 signaling normalizes the regenerative niche

Soares, Marc A; Cohen, Oriana D; Low, Yee Cheng; Sartor, Rita A; Ellison, Trevor; Anil, Utkarsh; Anzai, Lavinia; Chang, Jessica B; Saadeh, Pierre B; Rabbani, Piul S; Ceradini, Daniel J
Chronic hyperglycemia impairs intracellular redox homeostasis and contributes to impaired diabetic tissue regeneration. The Keap1/Nrf2 pathway is a critical regulator of the endogenous antioxidant response system and its dysfunction has been implicated in numerous pathologies. Here, we characterize the effect of chronic hyperglycemia on Nrf2 signaling within a diabetic cutaneous regeneration model. We characterized the effects of chronic hyperglycemia on the Keap1/Nrf2 pathway within models of diabetic cutaneous wound regeneration. We assessed reactive oxygen species (ROS) production and antioxidant gene expression following alterations in the Nrf2 suppressor, Keap1, and the subsequent changes in Nrf2 signaling. We also developed a topical siRNA-based therapy to restore redox homeostasis within diabetic wounds. Western blot demonstrated that chronic hyperglycemia-associated oxidative stress inhibits nuclear translocation of Nrf2 and impairs activation of antioxidant genes, thus contributing to ROS accumulation. Keap1 inhibition increased Nrf2 nuclear translocation, increased antioxidant gene expression, and reduced ROS production to normoglycemic levels, both in vitro and in vivo. Topical siKeap1 therapy resulted in improved regenerative capacity of diabetic wounds and accelerated closure. We report that chronic hyperglycemia weakens the endogenous antioxidant response and the consequences of this defect are manifested by intracellular redox dysregulation, which can be restored by Keap1 inhibition. Targeted siRNA-based therapy represents a novel, efficacious strategy to reestablish redox homeostasis and accelerate diabetic cutaneous tissue regeneration.
PMID: 26647385
ISSN: 1939-327x
CID: 1870072

Novel lipoproteoplex delivers Keap1 siRNA based gene therapy to accelerate diabetic wound healing

Rabbani, Piul S; Zhou, Anna; Borab, Zachary M; Frezzo, Joseph A; Srivastava, Nikita; More, Haresh T; Rifkin, William J; David, Joshua A; Berens, Samuel J; Chen, Raymond; Hameedi, Sophia; Junejo, Muhammad H; Kim, Camille; Sartor, Rita A; Liu, Che F; Saadeh, Pierre B; Montclare, Jin K; Ceradini, Daniel J
Therapeutics utilizing siRNA are currently limited by the availability of safe and effective delivery systems. Cutaneous diseases, specifically ones with significant genetic components are ideal candidates for topical siRNA based therapy but the anatomical structure of skin presents a considerable hurdle. Here, we optimized a novel liposome and protein hybrid nanoparticle delivery system for the topical treatment of diabetic wounds with severe oxidative stress. We utilized a cationic lipid nanoparticle (CLN) composed of 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) and the edge activator sodium cholate (NaChol), in a 6:1 ratio of DOTAP:NaChol (DNC). Addition of a cationic engineered supercharged coiled-coil protein (CSP) in a 10:1:1 ratio of DNC:CSP:siRNA produced a stable lipoproteoplex (LPP) nanoparticle, with optimal siRNA complexation, minimal cytotoxicity, and increased transfection efficacy. In a humanized murine diabetic wound healing model, our optimized LPP formulation successfully delivered siRNA targeted against Keap1, key repressor of Nrf2 which is a central regulator of redox mechanisms. Application of LPP complexing siKeap1 restored Nrf2 antioxidant function, accelerated diabetic tissue regeneration, and augmented reduction-oxidation homeostasis in the wound environment. Our topical LPP delivery system can readily be translated into clinical use for the treatment of diabetic wounds and can be extended to other cutaneous diseases with genetic components.
PMID: 28391065
ISSN: 1878-5905
CID: 2528042

Quantification of Facial Allograft Edema During Acute Rejection: A Software-Based 3-Dimensional Analysis [Case Report]

Boczar, Daniel; Brydges, Hilliard; Rodriguez Colon, Ricardo; Onuh, Ogechukwu C; Trilles, Jorge; Chaya, Bachar F; Gelb, Bruce; Ceradini, Daniel J; Rodriguez, Eduardo D
BACKGROUND:Acute rejection (AR) is a common complication in facial transplant (FT) patients associated with allograft edema and erythema. Our study aims to demonstrate the feasibility of using software-based 3-dimensional (3D) facial analysis to quantify edema as it resolves during/after AR treatment in an FT patient. METHODS:Our patient is a 23-year-old man who underwent a face and bilateral hand allotransplant in August 2020. The Vectra H1 (Canfield, Fairfield, NJ) portable scanner was used to capture 3D facial images at 8 time points between postoperative day (POD) 392 and 539. The images were analyzed with the Vectra Software using a rejection-free image (POD 539) as a control. RESULTS:Edema increased in the periorbital, lower third, and submandibular regions before AR treatment (POD 392-415). At POD 448, total facial edema was reduced to near baseline values in response to plasmapheresis and thymoglobulin (+156.94 to +28.2 mL). The fastest and most notable response to treatment was seen in the periorbital region, while some edema remained in the submandibular (+19.79 mL) and right lower third (+8.65 mL) regions. On POD 465, after the initial improvement, the edema increased but was resolved with steroid use. Facial edema did not correlate with the histopathological evaluation in our patient. CONCLUSIONS:We demonstrated the feasibility of analyzing 3D facial images to quantify edema during/after AR treatment in an FT patient. Our analysis detected edema changes consistent with AR followed by an improvement after treatment. This technology shows promise for noninvasive monitoring of FT patients.
PMID: 35993687
ISSN: 1536-3708
CID: 5312432

Measurements of motor functional outcomes in facial transplantation: A systematic review

Boczar, Daniel; Colon, Ricardo Rodriguez; Berman, Zoe P; Diep, Gustave K; Chaya, Bachar F; Trilles, Jorge; Gelb, Bruce E; Ceradini, Daniel J; Rodriguez, Eduardo D
Although the ethical and technical feasibility of face transplant (FT) has been established, current literature lacks consensus on functional outcomes monitoring for recipients. This systematic review aims to appraise and summarize the current literature on tools used to assess motor functional outcomes in FT. This study complied with the guidelines outlined in the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA). On September 15, 2020, two reviewers conducted independent electronic searches using medical literature databases, without language or time frame limitations. Eligibility criteria included studies reporting on the evaluation of motor functional outcomes in face transplant recipients. Of 451 papers found in the literature, 12 fulfilled the study inclusion criteria. The reported tools included clinical scales/examinations, electromyography, optical movement tracking devices, muscle volumetric measurement using magnetic resonance imaging, and software-based video and photo analyses. The frequency of data collection varied from every three months to every year. Publications reporting on motor functional outcomes tracking tools vary broadly and demonstrate a lack of consensus. Although quantitative measurements are desirable, adapted clinical scales are still the current standard of care.
PMID: 35965214
ISSN: 1878-0539
CID: 5299692

The First Successful Combined Full Face and Bilateral Hand Transplant

Ramly, Elie P; Alfonso, Allyson R; Berman, Zoe P; Diep, Gustave K; Bass, Jonathan L; Catalano, Louis W; Ceradini, Daniel J; Choi, Mihye; Cohen, Oriana D; Flores, Roberto L; Golas, Alyssa R; Hacquebord, Jacques H; Levine, Jamie P; Saadeh, Pierre B; Sharma, Sheel; Staffenberg, David A; Thanik, Vishal D; Rojas, Allison; Bernstein, G Leslie; Gelb, Bruce E; Rodriguez, Eduardo D
BACKGROUND:Vascularized composite allotransplantation (VCA) has redefined the frontiers of plastic and reconstructive surgery. At the cutting edge of this evolving paradigm, we present the first successful combined full face and bilateral hand transplant (FT-BHT). METHODS:A 21-year-old man with sequelae of an 80% total body surface area burn injury sustained following a motor vehicle accident presented for evaluation. The injury included full face and bilateral upper extremity composite tissue defects, resulting in reduced quality of life and loss of independence. Multidisciplinary evaluation confirmed eligibility for combined FT-BHT. The operative approach was validated through 11 cadaveric rehearsals utilizing computerized surgical planning. Institutional review board and organ procurement organization approvals were obtained. The recipient, his caregiver, and the donor family consented to the procedure. RESULTS:Combined full face (eyelids, ears, nose, lips, and skeletal subunits) and bilateral hand transplantation (forearm level) was performed over 23 hours on August 12-13th, 2020. Triple induction and maintenance immunosuppressive therapy and infection prophylaxis were administered. Plasmapheresis was necessary postoperatively. Minor revisions were performed over seven subsequent operations, including five left upper extremity, seven right upper extremity, and seven facial secondary procedures. At eight months, the patient is approaching functional independence and remains free of acute rejection. He has significantly improved range of motion, motor power, and sensation of the face and hand allografts. CONCLUSION/CONCLUSIONS:Combined FT-BHT is feasible. This is the most comprehensive VCA procedure successfully performed to date, marking a new milestone in plastic and reconstructive surgery for patients with otherwise irremediable injuries.
PMID: 35674521
ISSN: 1529-4242
CID: 5248392

Facial Transplantation: Principles and Evolving Concepts

Kantar, Rami S; Alfonso, Allyson R; Diep, Gustave K; Berman, Zoe P; Rifkin, William J; Diaz-Siso, J Rodrigo; Sosin, Michael; Gelb, Bruce E; Ceradini, Daniel J; Rodriguez, Eduardo D
LEARNING OBJECTIVES/OBJECTIVE:After studying this article, the participant should be able to: 1. Appreciate the evolution and increasing complexity of transplanted facial allografts over the past two decades. 2. Discuss indications and contraindications for facial transplantation, and donor and recipient selection criteria and considerations. 3. Discuss logistical, immunologic, and cost considerations in facial transplantation, in addition to emerging technologies used. 4. Understand surgical approaches and anatomical and technical nuances of the procedure. 5. Describe aesthetic, functional, and psychosocial outcomes of facial transplantation reported to date. SUMMARY/CONCLUSIONS:This CME article highlights principles and evolving concepts in facial transplantation. The field has witnessed significant advances over the past two decades, with more than 40 face transplants reported to date. The procedure now occupies the highest rung on the reconstructive ladder for patients with extensive facial disfigurement who are not amenable to autologous reconstructive approaches, in pursuit of optimal functional and aesthetic outcomes. Indications, contraindications, and donor and recipient considerations for the procedure are discussed. The authors also review logistical, immunologic, and cost considerations of facial transplantation. Surgical approaches to allograft procurement and transplantation, in addition to technical and anatomical nuances of the procedure, are provided. Finally, the authors review aesthetic, functional, and psychosocial outcomes that have been reported to date.
PMID: 34019516
ISSN: 1529-4242
CID: 4877732

Vascularized Composite Allotransplantation and Immunobiology: The Next Frontier

Jacoby, Adam; Cohen, Oriana; Gelb, Bruce E; Ceradini, Daniel J; Rodriguez, Eduardo D
PMID: 34019530
ISSN: 1529-4242
CID: 4877742

Predicting postoperative complications following mastectomy in the elderly: Evidence for the 5-factor frailty index

Dammeyer, Kristen; Alfonso, Allyson R; Diep, Gustave K; Kantar, Rami S; Berman, Zoe P; Daar, David A; Ramly, Elie P; Sosin, Michael; Ceradini, Daniel J
Understanding the risk factors that contribute to post-mastectomy complications can better inform preoperative discussions. Here, we assess the impact of the 5-Factor Frailty Index Score (mFI-5) in predicting 30-day postoperative complications in patients undergoing mastectomy. A retrospective review of the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) data base was conducted for patients older than 65 undergoing mastectomy between 2010 and 2015. We assessed each patient's Frailty Index Score using the mFI-5. Primary outcomes included wound complications and overall complications. Multivariate logistic and linear regression analyses were used to determine the ability of the mFI-5 to predict postoperative outcomes. A total of 13,783 patients were analyzed. The rate of wound complications was 3.0%, while the rate of overall complications was 6.0%. An mFI-5 score greater than 2 was an independent risk factor for wound complications and overall complications. Overall, patients undergoing mastectomy with an mFI-5 of 2 or greater experienced higher rates of postoperative complications. The mFI-5 is an accessible tool that can be used to risk-stratify patients undergoing mastectomy and can positively contribute to the informed consent and shared decision-making process.
PMID: 33650221
ISSN: 1524-4741
CID: 4801322

A noninvasive diagnostic approach for molecular monitoring of face transplant recipients [Meeting Abstract]

Snopkowski, C; Rabbani, P; Yang, H; Berman, Z; Diep, G; Li, C; Muthukumar, T; Ding, R; Ceradini, D; Suthanthiran, M
Purpose: Skin biopsies are currently the gold standard for evaluating the inflammatory status of face allografts. However, "tape stripping" is emerging as a noninvasive technique to monitor autoimmune/auto inflammatory skin diseases. This technique, highly suitable for serial sampling and combined with high sensitive PCR assays, could revolutionize molecular monitoring the face allograft status. Herein, we tested the hypothesis that isolation of total RNA and gene expression profiling are feasible using skin samples collected using tape strips.
Method(s): Tape strips (CuDerm Corporation, Texas) were used to obtain RNA from two face transplant recipients. Each tape strip is comprised of 10 discs. Allograft skin area was marked, cleaned with alcohol, and 8 samples (8 tape strips) were obtained. Each disc (10 discs from one sample) was immersed in 1ml RLT buffer with 100ul beta-mercaptoethanol. RNA was isolated from the tape strip skin samples using the RNeasy mini kit. We quantified total RNA using A260/A280 ratio, reverse transcribed RNA into cDNA and pre-amplified cDNA using oligonucleotide primer pairs for a custom panel of mRNAs. We measured absolute levels of mRNA for Keratin 15, MIP1alpha, and MIP1beta, as well as 18S rRNA by preamplification enhanced real time quantitative PCR assays (RT-qPCR assays) using Quant Studio 6. We designed gene specific Taqman primers and probes to amplify and detect gene of interest and a customized BAK amplicon to develop a standard curve for absolute quantification of transcript copies per microgram of total RNA.
Result(s): Median quantity of total RNA from the tape strips was 64.48ng. Individual and the median number of total RNA, individual and the median number of the reference gene 18S rRNA, and individual and median number of mRNA copies of Keratin 15, MIP1alpha, and MIP1beta are shown in Figure 1.
Conclusion(s): We have demonstrated the feasibility of isolating total RNA from tape strips and quantifying transcript abundance. Further refinement of this technology is ongoing in our laboratory. Tape strip based molecular monitoring of face transplant recipients may offer a noninvasive substitute for allograft biopsies
ISSN: 1600-6143
CID: 5180092