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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: 10 May 2024 | Viewed by 10374

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Special Issue Editor

Dr. Kun-Ming Chan

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Guest Editor

1. Division of General Surgery, Department of Surgery, Linkou Chang Gung Memorial Hospital, Guishan, Taoyuan, Taiwan
2. College of Medicine, Chang Gung University, Guishan, Taoyuan, Taiwan
Interests: surgery; liver and transplantation surgery

Special Issue Information

Dear Colleagues,

Transplantation has been a promising therapeutic option that offers a great chance of rescuing patients with end-stage organ diseases. However, numerous issues such as patient selection criteria, donor availability, graft rejection, and disease recurrence remain hotly debated for organ transplantation. Non-stop efforts in terms of basic science and clinical practice are still ongoing in order to optimize transplantation. Additionally, molecular biology remains the most important element in the foundation of transplantation.

Therefore, we invite authors to contribute original research or review articles on the topic of transplantation. In this Special Issue, we particularly take an interest in manuscripts that investigate and discuss the current status and limitations of transplantation in terms of molecular biology. Moreover, any innovations that could potentially facilitate the progress of this field in terms of pathogenesis, treatments, and prolongation of patient survival are encouraged. We welcome basic or translational studies, including discussions of molecular mechanisms and/or novel therapeutic strategies from real practice.

This Special Issue is supervised by Dr. Kun-Ming Chan and assisted by our Topical Advisory Panel Member (Dr. Rajani Dube).

Dr. Kun-Ming Chan
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

transplantation
donor
recipient
patient survival
graft

Published Papers (9 papers)

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Research

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14 pages, 2612 KiB

Open AccessArticle

Effect of Donor Age on Endocrine Function of and Immune Response to Ovarian Grafts

by Monica A. Wall, Mayara Garcia de Mattos Barbosa, Natalie Hanby, Michelle M. Cai, Margaret Brunette, Despina I. Pavlidis, Paula Arrowsmith, Ansen Q. Tan, Marilia Cascalho and Ariella Shikanov

Int. J. Mol. Sci. 2024, 25(6), 3431; https://doi.org/10.3390/ijms25063431 - 19 Mar 2024

Viewed by 659

Abstract

Premature loss of ovarian function (POI) is associated with numerous negative side effects, including vasomotor symptoms, sleep and mood disturbances, disrupted urinary function, and increased risks for osteoporosis and heart disease. Hormone replacement therapy (HRT), the standard of care for POI, delivers only a subset of ovarian hormones and fails to mimic the monthly cyclicity and daily pulsatility characteristic of healthy ovarian tissue in reproductive-aged individuals whose ovarian tissue contains thousands of ovarian follicles. Ovarian tissue allografts have the potential to serve as an alternative, cell-based HRT, capable of producing the full panel of ovarian hormones at physiologically relevant doses and intervals. However, the risks associated with systemic immune suppression (IS) required to prevent allograft rejection outweigh the potential benefits of comprehensive and dynamic hormone therapy. This work investigates whether the age of ovarian tissue donor animals affects the function of, and immune response to, subcutaneous ovarian grafts. We performed syngeneic and semi-allogeneic ovarian transplants using tissue from mice aged 6–8 (D7) or 20–22 (D21) days and evaluated ovarian endocrine function and immune response in a mouse model of POI. Our results revealed that tissue derived from D7 donors, containing an ample and homogeneous primordial follicle reserve, was more effective in fully restoring hypothalamic–pituitary–ovarian feedback. In contrast, tissue derived from D21 donors elicited anti-donor antibodies with higher avidity compared to tissue from younger donors, suggesting that greater immunogenicity may be a trade-off of using mature donors. This work contributes to our understanding of the criteria donor tissue must meet to effectively function as a cell-based HRT and explores the importance of donor age as a factor in ovarian allograft rejection. Full article

(This article belongs to the Special Issue Recent Advances in the Molecular Biology of Transplantation)

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16 pages, 1611 KiB

Open AccessArticle

Expression of Rejection-Associated Transcripts in Early Protocol Renal Transplant Biopsies Is Associated with Tacrolimus Exposure and Graft Outcome

by Betty Chamoun, Irina B. Torres, Alejandra Gabaldón, Thomas Jouvé, María Meneghini, José M. Zúñiga, Joana Sellarés, Manel Perelló, Daniel Serón, Oriol Bestard and Francesc Moreso

Int. J. Mol. Sci. 2024, 25(6), 3189; https://doi.org/10.3390/ijms25063189 - 10 Mar 2024

Viewed by 683

Abstract

Subclinical inflammation in protocol biopsies relates to tacrolimus exposure and human leukocyte antigen (HLA) matching. We aimed to characterize transcripts associated with rejection and tacrolimus exposure and the latter’s association with transplant outcomes. We tested whether gene expression is associated with rejection using strictly normal protocol biopsies (n = 17) and biopsies with T cell-mediated rejection (TCMR) or antibody-mediated rejection (ABMR) according to Banff criteria (n = 12). Subsequently, we analyzed these transcripts in a set of 4-month protocol biopsies (n = 137) to assess their association with donor and recipient characteristics, the intensity of immunosuppression, and the graft outcome. Differential expression (false discovery rate (FDR) < 0.01, fold (change (FC) > 3) between normal and rejection biopsies yielded a set of 111 genes. In the protocol biopsy cohort (n = 137), 19 out of these 111 genes correlated with tacrolimus trough levels at the time of biopsy (TAC-C₀), and unsupervised analysis split this cohort into two clusters. The two clusters differed in donor age and tacrolimus trough levels. Subclinical rejection, including borderline lesions, tended to occur in the same cluster. Logistic regression analysis indicated that TAC-C₀ at the time of biopsy (OR: 0.83, 95%CI:0.72–0.06, p = 0.0117) was associated with cluster 2. In a follow-up averaging 70 ± 30 months, this patient group displayed a significant decline in renal function (p = 0.0135). The expression of rejection-associated transcripts in early protocol biopsies is associated with tacrolimus exposure and a faster decline in renal function. Full article

(This article belongs to the Special Issue Recent Advances in the Molecular Biology of Transplantation)

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17 pages, 2311 KiB

Open AccessArticle

New Insights into Pediatric Kidney Transplant Rejection Biomarkers: Tissue, Plasma and Urine MicroRNAs Compared to Protocol Biopsy Histology

by Andrea Carraro, Piera De Gaspari, Benedetta Antoniello, Diana Marzenta, Emanuele Vianello, Benedetta Bussolati, Stefania Tritta, Federica Collino, Loris Bertoldi, Giuseppe Benvenuto, Luca Vedovelli, Elisa Benetti and Susanna Negrisolo

Int. J. Mol. Sci. 2024, 25(3), 1911; https://doi.org/10.3390/ijms25031911 - 05 Feb 2024

Viewed by 1006

Abstract

The early identification of a subclinical rejection (SCR) can improve the long-term outcome of the transplanted kidney through intensified immunosuppression. However, the only approved diagnostic method is the protocol biopsy, which remains an invasive method and not without minor and/or major complications. The protocol biopsy is defined as the sampling of allograft tissue at pre-established times even in the absence of an impaired renal function; however, it does not avoid histological damage. Therefore, the discovery of new possible biomarkers useful in the prevention of SCR has gained great interest. Among all the possible candidates, there are microRNAs (miRNAs), which are short, noncoding RNA sequences, that are involved in mediating numerous post-transcriptional pathways. They can be found not only in tissues, but also in different biological fluids, both as free particles and contained in extracellular vesicles (EVs) released by different cell types. In this study, we firstly performed a retrospective miRNA screening analysis on biopsies and serum EV samples of 20 pediatric transplanted patients, followed by a second screening on another 10 pediatric transplanted patients’ urine samples at one year post-transplant. In both cohorts, we divided the patients into two groups: patients with histological SCR and patients without histological SCR at one year post-transplantation. The isolated miRNAs were analyzed in an NGS platform to identify different expressions in the two allograft states. Although no statistical data were found in sera, in the tissue and urinary EVs, we highlighted signatures of miRNAs associated with the histological SCR state. Full article

(This article belongs to the Special Issue Recent Advances in the Molecular Biology of Transplantation)

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10 pages, 2589 KiB

Open AccessArticle

Significantly Improved Cold Preservation of Rat Hind Limb Vascularized Composite Allografts Using the New PrC-210 Free Radical Scavenger

by William E. Fahl, Zeeda H. Nkana, Maya M. Gitter, Weifeng Zeng and Aaron M. Dingle

Int. J. Mol. Sci. 2024, 25(3), 1609; https://doi.org/10.3390/ijms25031609 - 28 Jan 2024

Viewed by 662

Abstract

Vascularized composite allotransplantation (VCA) represents a promising reconstructive solution primarily conducted to improve quality of life. However, tissue damage caused by cold-ischemia (CI) storage prior to transplant represents a major factor limiting widespread application. This study investigates the addition of the novel free radical scavenger PrC-210 to UW Organ Preservation Solution (UW Solution) to suppress CI-induced skeletal muscle injury in a rat hind limb amputation model. Lewis rats received systemic perfusion of UW solution +/− PrC-210 (0 mM control, 10 mM, 20 mM, 30 mM, or 40 mM), followed by bilateral transfemoral amputation. Limbs were stored in 40 mL of the same perfusate at 4 °C for 48 h. Muscle punch biopsies were taken at set times over the 48 h cold-storage period and analyzed for caspase-3,7 activity, cytochrome C levels, and qualitative histology. A single 15 s perfusion of PrC-210-containing UW Solution conferred a dose-dependent reduction in CI-induced muscle cell death over 48 h. In the presence of PrC-210, muscle cell mitochondrial cytochrome C release was equivalent to 0 h controls, with profound reductions in the caspase-3,7 apoptotic marker that correlated with limb histology. PrC-210 conferred complete prevention of ROS-induced mitochondrial lysis in vitro, as measured by cytochrome C release. We conclude that the addition of 30 mM PrC210 to UW Solution conferred the most consistent reduction in CI limb damage, and it warrants further investigation for clinical application in the VCA setting. Full article

(This article belongs to the Special Issue Recent Advances in the Molecular Biology of Transplantation)

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14 pages, 3144 KiB

Open AccessArticle

Transcriptomic Changes in the Myocardium and Coronary Artery of Donation after Circulatory Death Hearts following Ex Vivo Machine Perfusion

by Lars Saemann, Kristin Wächter, Adrian-Iustin Georgevici, Sabine Pohl, Fabio Hoorn, Gábor Veres, Sevil Korkmaz-Icöz, Matthias Karck, Andreas Simm and Gábor Szabó

Int. J. Mol. Sci. 2024, 25(2), 1261; https://doi.org/10.3390/ijms25021261 - 19 Jan 2024

Viewed by 826

Abstract

Donation after circulatory death (DCD) hearts are predominantly maintained by normothermic blood perfusion (NBP). Nevertheless, it was shown that hypothermic crystalloid perfusion (HCP) is superior to blood perfusion to recondition left ventricular (LV) contractility. However, transcriptomic changes in the myocardium and coronary artery in DCD hearts after HCP and NBP have not been investigated yet. In a pig model, DCD hearts were harvested and maintained for 4 h by NBP (DCD-BP group, N = 8) or HCP with oxygenated histidine–tryptophane–ketoglutarate (HTK) solution (DCD-HTK, N = 8) followed by reperfusion with fresh blood for 2 h. In the DCD group (N = 8), hearts underwent reperfusion immediately after procurement. In the control group (N = 7), no circulatory death was induced. We performed transcriptomics from LV myocardial and left anterior descending (LAD) samples using microarrays (25,470 genes). We applied the Boruta algorithm for variable selection to identify relevant genes. In the DCD-BP group, compared to DCD, six genes were regulated in the myocardium and 1915 genes were regulated in the LAD. In the DCD-HTK group, 259 genes were downregulated in the myocardium and 27 in the LAD; and 52 genes were upregulated in the myocardium and 765 in the LAD, compared to the DCD group. We identified seven genes of relevance for group identification: ITPRIP, G3BP1, ARRDC3, XPO6, NOP2, SPTSSA, and IL-6. NBP resulted in the upregulation of genes involved in mitochondrial calcium accumulation and ROS production, the reduction in microvascular endothelial sprouting, and inflammation. HCP resulted in the downregulation of genes involved in NF-κB-, STAT3-, and SASP-activation and inflammation. Full article

(This article belongs to the Special Issue Recent Advances in the Molecular Biology of Transplantation)

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17 pages, 2926 KiB

Open AccessArticle

Single-Cell RNA Sequencing of Donor-Reactive T Cells Reveals Role of Apoptosis in Donor-Specific Hyporesponsiveness of Kidney Transplant Recipients

by Amy C. J. van der List, Nicolle H. R. Litjens, Rutger W. W. Brouwer, Mariska Klepper, Alexander T. den Dekker, Wilfred F. J. van Ijcken and Michiel G. H. Betjes

Int. J. Mol. Sci. 2023, 24(19), 14463; https://doi.org/10.3390/ijms241914463 - 23 Sep 2023

Cited by 1 | Viewed by 1069

Abstract

After kidney transplantation (KT), donor-specific hyporesponsiveness (DSH) of recipient T cells develops over time. Recently, apoptosis was identified as a possible underlying mechanism. In this study, both transcriptomic profiles and complete V(D)J variable regions of TR transcripts from individual alloreactive T cells of kidney transplant recipients were determined with single-cell RNA sequencing. Alloreactive T cells were identified by CD137 expression after stimulation of peripheral blood mononuclear cells obtained from KT recipients (N = 7) prior to and 3–5 years after transplantation with cells of their donor or a third party control. The alloreactive T cells were sorted, sequenced and the transcriptome and T cell receptor profiles were analyzed using unsupervised clustering. Alloreactive T cells retain a highly polyclonal T Cell Receptor Alpha/Beta repertoire over time. Post transplantation, donor-reactive CD4+ T cells had a specific downregulation of genes involved in T cell cytokine-mediated pathways and apoptosis. The CD8+ donor-reactive T cell profile did not change significantly over time. Single-cell expression profiling shows that activated and pro-apoptotic donor-reactive CD4+ T cell clones are preferentially lost after transplantation in stable kidney transplant recipients. Full article

(This article belongs to the Special Issue Recent Advances in the Molecular Biology of Transplantation)

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18 pages, 3301 KiB

Open AccessArticle

Cold Storage Followed by Transplantation Induces Interferon-Gamma and STAT-1 in Kidney Grafts

by Madison McGraw, David Miller, Sorena Lo and Nirmala Parajuli

Int. J. Mol. Sci. 2023, 24(6), 5468; https://doi.org/10.3390/ijms24065468 - 13 Mar 2023

Cited by 2 | Viewed by 1510

Abstract

Cold storage (CS)-mediated inflammation, a reality of donor kidney processing and transplantation, can contribute to organ graft failure. However, the mechanisms by which this inflammation is perpetuated during and after CS remain unclear. Here, we examined the immunoregulatory roles of signal transducer and activator of transcription (STAT) family proteins, most notably STAT1 and STAT3, with our in vivo model of renal CS and transplant. Donor rat kidneys were exposed to 4 h or 18 h of CS, which was then followed by transplantation (CS + transplant). STAT total protein level and activity (phosphorylation) were evaluated via Western blot analysis and mRNA expression was tabulated using quantitative RT-PCR after organ harvest on day 1 or day 9 post-surgery. In vivo assays were further corroborated via similar analyses featuring in vitro models, specifically proximal tubular cells (human and rat) as well as macrophage cells (Raw 264.7). Strikingly, gene expression of IFN-γ (a pro-inflammatory cytokine inducer of STAT) and STAT1 were markedly increased after CS + transplant. STAT3 dephosphorylation was additionally observed after CS, a result suggestive of dysregulation of anti-inflammatory signaling as phosphorylated STAT3 acts as a transcription factor in the nucleus to increase the expression of anti-inflammatory signaling molecules. In vitro, IFN-γ gene expression as well as amplification of downstream STAT1 and inducible nitric oxide synthase (iNOS; a hallmark of ischemia reperfusion injury) was remarkably increased after CS + rewarming. Collectively, these results demonstrate that aberrant induction of STAT1 is sustained in vivo post-CS exposure and post-transplant. Thus, Jak/STAT signaling may be a viable therapeutic target during CS to mitigate poor graft outcomes when transplanting kidneys from deceased donors. Full article

(This article belongs to the Special Issue Recent Advances in the Molecular Biology of Transplantation)

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Review

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24 pages, 392 KiB

Open AccessReview

Modification of Preservative Fluids with Antioxidants in Terms of Their Efficacy in Liver Protection before Transplantation

by Aneta Ostróżka-Cieślik

Int. J. Mol. Sci. 2024, 25(3), 1850; https://doi.org/10.3390/ijms25031850 - 03 Feb 2024

Viewed by 935

Abstract

Transplantation is currently the only effective treatment for patients with end-stage liver failure. In recent years, many advanced studies have been conducted to improve the efficiency of organ preservation techniques. Modifying the composition of the preservation fluids currently used may improve graft function and increase the likelihood of transplantation success. The modified fluid is expected to extend the period of safe liver storage in the peri-transplantation period and to increase the pool of organs for transplantation with livers from marginal donors. This paper provides a literature review of the effects of antioxidants on the efficacy of liver preservation fluids. Medline (PubMed), Scopus, and Cochrane Library databases were searched using a combination of MeSH terms: “liver preservation”, “transplantation”, “preservation solution”, “antioxidant”, “cold storage”, “mechanical perfusion”, “oxidative stress”, “ischemia-reperfusion injury”. Studies published up to December 2023 were included in the analysis, with a focus on publications from the last 30 years. A total of 45 studies met the inclusion criteria. The chemical compounds analyzed showed mostly bioprotective effects on hepatocytes, including but not limited to multifactorial antioxidant and free radical protective effects. It should be noted that most of the information cited is from reports of studies conducted in animal models, most of them in rodents. Full article

(This article belongs to the Special Issue Recent Advances in the Molecular Biology of Transplantation)

25 pages, 1243 KiB

Open AccessReview

Liquid Biopsy in Hepatocellular Carcinoma: The Significance of Circulating Tumor Cells in Diagnosis, Prognosis, and Treatment Monitoring

by Mohammed Rifat Shaik, Prem Raj Sagar, Nishat Anjum Shaik and Navkiran Randhawa

Int. J. Mol. Sci. 2023, 24(13), 10644; https://doi.org/10.3390/ijms241310644 - 26 Jun 2023

Cited by 4 | Viewed by 1783

Abstract

Hepatocellular carcinoma (HCC) is an aggressive malignancy with poor outcomes when diagnosed at an advanced stage. Current curative treatments are most effective in early-stage HCC, highlighting the importance of early diagnosis and intervention. However, existing diagnostic methods, such as radiological imaging, alpha-fetoprotein (AFP) testing, and biopsy, have limitations that hinder early diagnosis. AFP elevation is absent in a significant portion of tumors, and imaging may have low sensitivity for smaller tumors or in the presence of cirrhosis. Additionally, as our understanding of the molecular pathogenesis of HCC grows, there is an increasing need for molecular information about the tumors. Biopsy, although informative, is invasive and may not always be feasible depending on tumor location. In this context, liquid biopsy technology has emerged as a promising approach for early diagnosis, enabling molecular characterization and genetic profiling of tumors. This technique involves analyzing circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), or tumor-derived exosomes. CTCs are cancer cells shed from the primary tumor or metastatic sites and circulate in the bloodstream. Their presence not only allows for early detection but also provides insights into tumor metastasis and recurrence. By detecting CTCs in peripheral blood, real-time tumor-related information at the DNA, RNA, and protein levels can be obtained. This article provides an overview of CTCs and explores their clinical significance for early detection, prognosis, treatment selection, and monitoring treatment response in HCC, citing relevant literature. Full article

(This article belongs to the Special Issue Recent Advances in the Molecular Biology of Transplantation)

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Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Planned paper: Gene expression transcriptome profile on endomyocardial biopsies, a methodological validation study- Dr. Alessia Giarraputo(Submission date to be determined)

Planned paper: Role of GZMK and IL7R to discriminate infection from rejection in post transplanted patients: a FFPE-based transcriptome analysis- Dr. Alessia Giarraputo(Submission date to be determined)

Planned Paper: A20 in kidney transplantation and autoimmunity- Dr. Julia Weinmann-Menke(30 Jan 2024)

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