MicroRNA signatures in cardiac biopsies and detection of allograft rejection

Andrea Di Francesco, Marny Fedrigo, Donato Santovito, Lucia Natarelli, Chiara Castellani, Fabio De Pascale, Giuseppe Toscano, Angela Fraiese, Giuseppe Feltrin, Elena Benazzi, Angela Nocco, Gaetano Thiene, Marialuisa Valente, Giorgio Valle, Andreas Schober, Gino Gerosa, Annalisa Angelini

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

BACKGROUND: Identification of heart transplant (HTx) rejection currently relies on immunohistology and immunohistochemistry. We aimed to identify specific sets of microRNAs (miRNAs) to characterize acute cellular rejection (ACR), antibody-mediated rejection (pAMR), and mixed rejection (MR) in monitoring formalin-fixed paraffin-embedded (FFPE) endomyocardial biopsies (EMBs) in HTx patients. METHODS: In this study we selected 33 adult HTx patients. For each, we chose the first positive EMB for study of each type of rejection. The next-generation sequencing (NGS) IonProton technique and reverse transcript quantitative polymerase chain reaction (RT-qPCR) analysis were performed on FFPE EMBs. Using logistic regression analysis we created unique miRNA signatures as predictive models of each rejection. In situ PCR was carried out on the same EMBs. RESULTS: We obtained >2,257 mature miRNAs from all the EMBs. The 3 types of rejection showed a different miRNA profile for each group. The logistic regression model formed by miRNAs 208a, 126-5p, and 135a-5p identified MR; that formed by miRNAs 27b-3p, 29b-3p, and 199a-3p identified ACR; and that formed by miRNAs 208a, 29b-3p, 135a-5p, and 144-3p identified pAMR. The expression of miRNAs on tissue, through in situ PCR, showed different expressions of the same miRNA in different rejections. miRNA 126-5p was expressed in endothelial cells in ACR but in cardiomyocytes in pAMR. In ACR, miRNA 29b-3p was significantly overexpressed and detected in fibroblasts, whereas in pAMR it was underexpressed and detected only in cardiomyocytes. CONCLUSIONS: miRNA profiling on FFPE EMBs differentiates the 3 types of rejection. Localization of expression of miRNAs on tissue showed different expression of the same miRNA for different cells, suggesting different roles of the same miRNA in different rejections.

Original languageEnglish
Pages (from-to)1329-1340
JournalJournal of Heart and Lung Transplantation
Volume37
Issue number11
DOIs
Publication statusPublished - 2018

Fingerprint

MicroRNAs
Allografts
Biopsy
Paraffin
Formaldehyde
Logistic Models
Cardiac Myocytes
Polymerase Chain Reaction
Graft Rejection
Endothelial Cells
Fibroblasts
Immunohistochemistry

Keywords

  • acute cellular rejection
  • antibody-mediated rejection
  • HTx EMBs
  • mixed rejection
  • NGS miRNA profiling

ASJC Scopus subject areas

  • Surgery
  • Pulmonary and Respiratory Medicine
  • Cardiology and Cardiovascular Medicine
  • Transplantation

Cite this

Di Francesco, A., Fedrigo, M., Santovito, D., Natarelli, L., Castellani, C., De Pascale, F., ... Angelini, A. (2018). MicroRNA signatures in cardiac biopsies and detection of allograft rejection. Journal of Heart and Lung Transplantation, 37(11), 1329-1340. https://doi.org/10.1016/j.healun.2018.06.010

MicroRNA signatures in cardiac biopsies and detection of allograft rejection. / Di Francesco, Andrea; Fedrigo, Marny; Santovito, Donato; Natarelli, Lucia; Castellani, Chiara; De Pascale, Fabio; Toscano, Giuseppe; Fraiese, Angela; Feltrin, Giuseppe; Benazzi, Elena; Nocco, Angela; Thiene, Gaetano; Valente, Marialuisa; Valle, Giorgio; Schober, Andreas; Gerosa, Gino; Angelini, Annalisa.

In: Journal of Heart and Lung Transplantation, Vol. 37, No. 11, 2018, p. 1329-1340.

Research output: Contribution to journalArticle

Di Francesco, A, Fedrigo, M, Santovito, D, Natarelli, L, Castellani, C, De Pascale, F, Toscano, G, Fraiese, A, Feltrin, G, Benazzi, E, Nocco, A, Thiene, G, Valente, M, Valle, G, Schober, A, Gerosa, G & Angelini, A 2018, 'MicroRNA signatures in cardiac biopsies and detection of allograft rejection', Journal of Heart and Lung Transplantation, vol. 37, no. 11, pp. 1329-1340. https://doi.org/10.1016/j.healun.2018.06.010
Di Francesco A, Fedrigo M, Santovito D, Natarelli L, Castellani C, De Pascale F et al. MicroRNA signatures in cardiac biopsies and detection of allograft rejection. Journal of Heart and Lung Transplantation. 2018;37(11):1329-1340. https://doi.org/10.1016/j.healun.2018.06.010
Di Francesco, Andrea ; Fedrigo, Marny ; Santovito, Donato ; Natarelli, Lucia ; Castellani, Chiara ; De Pascale, Fabio ; Toscano, Giuseppe ; Fraiese, Angela ; Feltrin, Giuseppe ; Benazzi, Elena ; Nocco, Angela ; Thiene, Gaetano ; Valente, Marialuisa ; Valle, Giorgio ; Schober, Andreas ; Gerosa, Gino ; Angelini, Annalisa. / MicroRNA signatures in cardiac biopsies and detection of allograft rejection. In: Journal of Heart and Lung Transplantation. 2018 ; Vol. 37, No. 11. pp. 1329-1340.
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T1 - MicroRNA signatures in cardiac biopsies and detection of allograft rejection

AU - Di Francesco, Andrea

AU - Fedrigo, Marny

AU - Santovito, Donato

AU - Natarelli, Lucia

AU - Castellani, Chiara

AU - De Pascale, Fabio

AU - Toscano, Giuseppe

AU - Fraiese, Angela

AU - Feltrin, Giuseppe

AU - Benazzi, Elena

AU - Nocco, Angela

AU - Thiene, Gaetano

AU - Valente, Marialuisa

AU - Valle, Giorgio

AU - Schober, Andreas

AU - Gerosa, Gino

AU - Angelini, Annalisa

PY - 2018

Y1 - 2018

N2 - BACKGROUND: Identification of heart transplant (HTx) rejection currently relies on immunohistology and immunohistochemistry. We aimed to identify specific sets of microRNAs (miRNAs) to characterize acute cellular rejection (ACR), antibody-mediated rejection (pAMR), and mixed rejection (MR) in monitoring formalin-fixed paraffin-embedded (FFPE) endomyocardial biopsies (EMBs) in HTx patients. METHODS: In this study we selected 33 adult HTx patients. For each, we chose the first positive EMB for study of each type of rejection. The next-generation sequencing (NGS) IonProton technique and reverse transcript quantitative polymerase chain reaction (RT-qPCR) analysis were performed on FFPE EMBs. Using logistic regression analysis we created unique miRNA signatures as predictive models of each rejection. In situ PCR was carried out on the same EMBs. RESULTS: We obtained >2,257 mature miRNAs from all the EMBs. The 3 types of rejection showed a different miRNA profile for each group. The logistic regression model formed by miRNAs 208a, 126-5p, and 135a-5p identified MR; that formed by miRNAs 27b-3p, 29b-3p, and 199a-3p identified ACR; and that formed by miRNAs 208a, 29b-3p, 135a-5p, and 144-3p identified pAMR. The expression of miRNAs on tissue, through in situ PCR, showed different expressions of the same miRNA in different rejections. miRNA 126-5p was expressed in endothelial cells in ACR but in cardiomyocytes in pAMR. In ACR, miRNA 29b-3p was significantly overexpressed and detected in fibroblasts, whereas in pAMR it was underexpressed and detected only in cardiomyocytes. CONCLUSIONS: miRNA profiling on FFPE EMBs differentiates the 3 types of rejection. Localization of expression of miRNAs on tissue showed different expression of the same miRNA for different cells, suggesting different roles of the same miRNA in different rejections.

AB - BACKGROUND: Identification of heart transplant (HTx) rejection currently relies on immunohistology and immunohistochemistry. We aimed to identify specific sets of microRNAs (miRNAs) to characterize acute cellular rejection (ACR), antibody-mediated rejection (pAMR), and mixed rejection (MR) in monitoring formalin-fixed paraffin-embedded (FFPE) endomyocardial biopsies (EMBs) in HTx patients. METHODS: In this study we selected 33 adult HTx patients. For each, we chose the first positive EMB for study of each type of rejection. The next-generation sequencing (NGS) IonProton technique and reverse transcript quantitative polymerase chain reaction (RT-qPCR) analysis were performed on FFPE EMBs. Using logistic regression analysis we created unique miRNA signatures as predictive models of each rejection. In situ PCR was carried out on the same EMBs. RESULTS: We obtained >2,257 mature miRNAs from all the EMBs. The 3 types of rejection showed a different miRNA profile for each group. The logistic regression model formed by miRNAs 208a, 126-5p, and 135a-5p identified MR; that formed by miRNAs 27b-3p, 29b-3p, and 199a-3p identified ACR; and that formed by miRNAs 208a, 29b-3p, 135a-5p, and 144-3p identified pAMR. The expression of miRNAs on tissue, through in situ PCR, showed different expressions of the same miRNA in different rejections. miRNA 126-5p was expressed in endothelial cells in ACR but in cardiomyocytes in pAMR. In ACR, miRNA 29b-3p was significantly overexpressed and detected in fibroblasts, whereas in pAMR it was underexpressed and detected only in cardiomyocytes. CONCLUSIONS: miRNA profiling on FFPE EMBs differentiates the 3 types of rejection. Localization of expression of miRNAs on tissue showed different expression of the same miRNA for different cells, suggesting different roles of the same miRNA in different rejections.

KW - acute cellular rejection

KW - antibody-mediated rejection

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KW - mixed rejection

KW - NGS miRNA profiling

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