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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

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

Hepatic Artery Microvascular Anastomosis in Liver Transplantation: A Systematic Review of the Literature

Kantar, Rami S; Berman, Zoe P; Diep, Gustave K; Ramly, Elie P; Alfonso, Allyson R; Sosin, Michael; Lee, Z-Hye; Rifkin, William J; Kaoutzanis, Christodoulos; Yu, Jason W; Ceradini, Daniel J; Dagher, Nabil N; Levine, Jamie P
BACKGROUND:The operating microscope is used in many centers for microvascular hepatic arterial reconstruction in living as well as deceased donor liver transplantation in adult and pediatric recipients. To date, a systematic review of the literature examining this topic is lacking. METHODS:This systematic review of the literature was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. Three different electronic databases (PubMed, Embase OVID, and Cochrane CENTRAL) were queried. RESULTS:A total of 34 studies were included. The rate of hepatic artery thrombosis (HAT) in noncomparative studies (28) ranged from 0% to 10%, with 8 studies reporting patient deaths resulting from HAT. Within comparative studies, the rate of HAT in patients who underwent arterial reconstruction using the operating microscope ranged from 0% to 5.3%, whereas the rate of HAT in patients who underwent arterial reconstruction using loupe magnification ranged from 0% up to 28.6%, and 2 studies reported patient deaths resulting from HAT. Two comparative studies did not find statistically significant differences between the 2 groups. CONCLUSIONS:Our comprehensive systematic review of the literature seems to suggest that overall, rates of HAT may be lower when the operating microscope is used for hepatic arterial reconstruction in liver transplantation. However, matched comparisons are lacking and surgical teams need to be mindful of the learning curve associated with the use of the operating microscope as compared with loupe magnification, as well as the logistical and time constraints associated with setup of the operating microscope.
PMID: 33315357
ISSN: 1536-3708
CID: 4717562

Keratinocyte-Macrophage Crosstalk by the Nrf2/Ccl2/EGF Signaling Axis Orchestrates Tissue Repair

Villarreal-Ponce, Alvaro; Tiruneh, Melat Worku; Lee, Jasmine; Guerrero-Juarez, Christian F; Kuhn, Joseph; David, Joshua A; Dammeyer, Kristen; Mc Kell, Renee; Kwong, Jennifer; Rabbani, Piul S; Nie, Qing; Ceradini, Daniel J
Unveiling the molecular mechanisms underlying tissue regeneration provides new opportunities to develop treatments for diabetic ulcers and other chronic skin lesions. Here, we show that Ccl2 secretion by epidermal keratinocytes is directly orchestrated by Nrf2, a prominent transcriptional regulator of tissue regeneration that is activated early after cutaneous injury. Through a unique feedback mechanism, we find that Ccl2 from epidermal keratinocytes not only drives chemotaxis of macrophages into the wound but also triggers macrophage expression of EGF, which in turn activates basal epidermal keratinocyte proliferation. Notably, we find dysfunctional activation of Nrf2 in epidermal keratinocytes of diabetic mice after wounding, which partly explains regenerative impairments associated with diabetes. These findings provide mechanistic insight into the critical relationship between keratinocyte and macrophage signaling during tissue repair, providing the basis for continued investigation of the therapeutic value of Nrf2.
PMID: 33238115
ISSN: 2211-1247
CID: 4680802

Nrf2-activating Therapy Accelerates Wound Healing in a Model of Cutaneous Chronic Venous Insufficiency

Kuhn, Joseph; Sultan, Darren L; Waqas, Bukhtawar; Ellison, Trevor; Kwong, Jennifer; Kim, Camille; Hassan, Absara; Rabbani, Piul S; Ceradini, Daniel J
Chronic venous insufficiency (CVI) stems from venous hypertension, extravasation of blood, and iron-rich skin deposits. The latter is central to ulcer development through generating reactive oxygen species (ROS) that drive persistent local inflammation and the development of lipodermatosclerosis. The ability to study CVI cutaneous inflammation is fundamental to advancing therapies. To address this end, a novel protocol was adapted to investigate cutaneous wound healing in iron-induced inflammation.
PMID: 33299679
ISSN: 2169-7574
CID: 4709092

Communication Efficiency in a Face Transplant Recipient: Determinants and Therapeutic Implications

Levy-Lambert, Dina; Grigos, Maria I; LeBlanc, Étoile; DeMitchell-Rodriguez, Evellyn M; Noel, Daphney Y; Alfonso, Allyson R; Ramly, Elie P; Rifkin, William J; Diaz-Siso, J Rodrigo; Ceradini, Daniel J; Kantar, Rami S; Rodriguez, Eduardo D
We longitudinally assessed speech intelligibility (percent words correct/pwc), communication efficiency (intelligible words per minute/iwpm), temporal control markers (speech and pause coefficients of variation), and formant frequencies associated with lip motion in a 41-year-old face transplant recipient. Pwc and iwpm at 13 months post-transplantation were both higher than preoperative values. Multivariate regression demonstrated that temporal markers and all formant frequencies associated with lip motion were significant predictors (P < 0.05) of communication efficiency, highlighting the interplay of these variables in generating intelligible and effective speech. These findings can guide us in developing personalized rehabilitative approaches in face transplant recipients for optimal speech outcomes.
PMID: 32649536
ISSN: 1536-3732
CID: 4517332