Improving the ischemia-reperfusion injury in vascularized composite allotransplantation: Clinical experience and experimental implications

Solid organ and composite tissue allotransplanation have been widely applied to treat end-stage organ failure and massive tissue defects, respectively. Currently there are a lot of research endeavors focusing on induction of transplantation tolerance, to relieve the burden derived from long-term immunosuppressant uptake. The mesenchymal stromal cells (MSCs) have been demonstrated with potent immunomodulatory capacities and applied as promising cellular therapeutics to promote allograft survival and induce tolerance. As a rich source of adult MSCs, adipose tissue provides additional advantages of easy accessibility and good safety profile. In recent years, the stromal vascular fraction (SVF) isolated from adipose tissues following enzymatic or mechanical processing without in vitro culture and expansion has demonstrated immunomodulatory and proangiogenic properties. Furthermore, the secretome of AD-MSCs has been utilized in transplantation field as a potential “cell-free” therapeutics. This article reviews recent studies that employ these adipose-derived therapeutics, including AD-MSCs, SVF, and secretome, in various aspects of organ and tissue allotransplantation. Most reports validate their efficacies in prolonging allograft survival. Specifically, the SVF and secretome have performed well for graft preservation and pretreatment, potentially through their proangiogenic and antioxidative capacities. In contrast, AD-MSCs were suitable for peri-transplantation immunosuppression. The proper combination of AD-MSCs, lymphodepletion and conventional immunosuppressants could consistently induce donor-specific tolerance to vascularized composite allotransplants (VCA). For each type of transplantation, optimizing the choice of therapeutics, timing, dose, and frequency of administration may be required. Future progress in the application of adipose-derived therapeutics to induce transplantation tolerance will be further benefited by continued research into their mechanisms of action and the development of standardized protocols for isolation methodologies, cell culture, and efficacy evaluation.

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“…rejection after transplantation. Therefore, effective management of IRI may promote allograft survival and suppress rejection (69).…”

Section: Roles Of Adipose Tissue-derived Therapeutics In Allotranspla...mentioning

confidence: 99%

Toward transplantation tolerance with adipose tissue-derived therapeutics

et al. 2023

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“…While the refinements of microsurgical techniques allow for adequate restoration of macrovascular perfusion from the pedicle, ischemia and ischemia-reperfusion injury (IRI) compromise microvascular circulation and can result in necrosis of the distal flap (Krauss et al, 2018). Reperfusion injury also impacts acute and chronic rejection of allografts through activation of inflammatory pathways (He et al, 2022).…”

Section: Introductionmentioning

confidence: 99%

Systematic review of pathologic markers in skin ischemia with and without reperfusion injury in microsurgical reconstruction: Biomarker alterations precede histological structure changes

Khalaf,

Duarte Bateman,

Reyes

et al. 2024

Microsurgery

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BackgroundIschemia and ischemia–reperfusion injury contribute to partial or complete flap necrosis. Traditionally, skin histology has been used to evaluate morphological and structural changes, however histology does not detect early changes. We hypothesize that morphological and structural skin changes in response to ischemia and IRI occur late, and modification of gene and protein expression are the earliest changes in ischemia and IRI.MethodsA systematic review was performed in accordance with PRISMA guidelines. Studies reporting skin histology or gene/protein expression changes following ischemia with or without reperfusion injury published between 2002 and 2022 were included. The primary outcomes were descriptive and semi‐quantitative histological structural changes, leukocyte infiltration, edema, vessel density; secondary outcomes were quantitative gene and protein expression intensity (PCR and western blot). Model type, experimental intervention, ischemia method and duration, reperfusion duration, biopsy location and time point were collected.ResultsOne hundred and one articles were included. Hematoxylin and eosin (H&E) showed inflammatory infiltration in early responses (12–24 h), with structural modifications (3–14 days) and neovascularization (5–14 days) as delayed responses. Immunohistochemistry (IHC) identified angiogenesis (CD31, CD34), apoptosis (TUNEL, caspase‐3, Bax/Bcl‐2), and protein localization (NF‐κB). Gene (PCR) and protein expression (western blot) detected inflammation and apoptosis; endoplasmic reticulum stress/oxidative stress and hypoxia; and neovascularization. The most common markers were TNF‐α, IL‐6 and IL‐1β (inflammation), caspase‐3 (apoptosis), VEGF (neovascularization), and HIF‐1α (hypoxia).ConclusionThere is no consensus or standard for reporting skin injury during ischemia and IRI. H&E histology is most frequently performed but is primarily descriptive and lacks sensitivity for early skin injury. Immunohistochemistry and gene/protein expression reveal immediate and quantitative cellular responses to skin ischemia and IRI. Future research is needed towards a universally‐accepted skin injury scoring system.

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“…Static cold storage has given way to the perfusion machine for several solid organs, so much so that it has become the clinical standard in some centers 1 – 5 . The objective is to improve the quality of transplanted organs by reducing the ischemic damage and ischemia–reperfusion injuries 6 – 8 that lead to increased inflammation and a heightened host immune response. An even more ambitious goal is to optimize perfusion extended to several days, with multiple potential clinical applications: Extended preservation would allow for improved cross-matching between donor and recipient by enabling long-distance transport 9 – 11 , potentially to the other side of the globe.…”

Section: Introductionmentioning

confidence: 99%

“…In this work, to evaluate the feasibility and challenges of VCA preservation by supercooling, an initial study with porcine partial hindlimbs was performed. The results were compared with cold static storage, which remains the gold standard in VCA preservation 8 .…”

Section: Introductionmentioning

confidence: 99%

VCA supercooling in a swine partial hindlimb model

Berkane,

Filz von Reiterdank,

Tawa

et al. 2024

Sci Rep

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Vascularized composite allotransplantations are complex procedures with substantial functional impact on patients. Extended preservation of VCAs is of major importance in advancing this field. It would result in improved donor-recipient matching as well as the potential for ex vivo manipulation with gene and cell therapies. Moreover, it would make logistically feasible immune tolerance induction protocols through mixed chimerism. Supercooling techniques have shown promising results in multi-day liver preservation. It consists of reaching sub-zero temperatures while preventing ice formation within the graft by using various cryoprotective agents. By drastically decreasing the cell metabolism and need for oxygen and nutrients, supercooling allows extended preservation and recovery with lower ischemia–reperfusion injuries. This study is the first to demonstrate the supercooling of a large animal model of VCA. Porcine hindlimbs underwent 48 h of preservation at − 5 °C followed by recovery and normothermic machine perfusion assessment, with no issues in ice formation and favorable levels of injury markers. Our findings provide valuable preliminary results, suggesting a promising future for extended VCA preservation.

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Improving the ischemia-reperfusion injury in vascularized composite allotransplantation: Clinical experience and experimental implications

Cited by 9 publications

References 196 publications

Toward transplantation tolerance with adipose tissue-derived therapeutics

Toward transplantation tolerance with adipose tissue-derived therapeutics

Systematic review of pathologic markers in skin ischemia with and without reperfusion injury in microsurgical reconstruction: Biomarker alterations precede histological structure changes

VCA supercooling in a swine partial hindlimb model

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