Circulating cell-free DNA as a biomarker of tissue injury: Assessment in a cardiac xenotransplantation model

Sean Agbor-Enoh, Joshua L. Chan, Avneesh Singh, Ilker Tunc, Sasha Gorham, Jun Zhu, Mehdi Pirooznia, Philip C. Corcoran, Marvin L. Thomas, Billeta G.T. Lewis, Moon Kyoo Jang, David L. Ayares, Keith A. Horvath, Muhammad M. Mohiuddin, Hannah Valantine

Research output: Contribution to journalArticle

Abstract

Background: Observational studies suggest that cell‐free DNA (cfDNA) is a biomarker of tissue injury in a range of conditions including organ transplantation. However, the lack of model systems to study cfDNA and its relevance to tissue injury has limited the advancements in this field. We hypothesized that the predictable course of acute humoral xenograft rejection (AHXR) in organ transplants from genetically engineered donors provides an ideal system for assessing circulating cfDNA as a marker of tissue injury. Methods: Heterotopic heart xenotransplantation was pre-transplantation on baboons (n = 7) using genetically modified pig donor hearts. Plasma cfDNA pre-transplant and at serial times post‐transplantation (n = 75) were shotgun sequenced. After alignment of sequence reads to pig and baboon reference sequences, we computed the percentage of xenograft-derived cfDNA (xdcfDNA) relative to recipient by counting uniquely aligned pig and baboon sequence reads. Results: The xdcfDNA percentage was high early post-transplantation and decayed exponentially to low stable levels (baseline); the decay half-life was 3.0 days. Post-transplantation baseline xdcfDNA levels were higher for transplant recipients that subsequently developed graft loss than in the 1 animal that did not reject the graft (3.2% vs 0.5%). Elevations in xdcfDNA percentage coincided with increased troponin and clinical evidence of rejection. Importantly, elevations in xdcfDNA percentage preceded clinical signs of rejection or increases in troponin levels. Conclusion: Cross‐species xdcfDNA kinetics in relation to acute rejection are similar to the patterns in human allografts. These observations in a xenotransplantation model support the body of evidence suggesting that circulating cfDNA is a marker of tissue injury.

Original languageEnglish (US)
JournalJournal of Heart and Lung Transplantation
DOIs
StateAccepted/In press - Jan 1 2018
Externally publishedYes

Fingerprint

Heterologous Transplantation
Heterografts
Biomarkers
Papio
DNA
Wounds and Injuries
Transplants
Troponin
Swine
Transplantation
Tissue Donors
Sequence Alignment
Firearms
Organ Transplantation
Observational Studies
Allografts
Half-Life

Keywords

  • acute humoral xenograft rejection
  • biomarker
  • cell-free DNA
  • cell-free DNA models
  • genetically engineered donors
  • tissue injury
  • xenotransplantation

ASJC Scopus subject areas

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

Cite this

Circulating cell-free DNA as a biomarker of tissue injury : Assessment in a cardiac xenotransplantation model. / Agbor-Enoh, Sean; Chan, Joshua L.; Singh, Avneesh; Tunc, Ilker; Gorham, Sasha; Zhu, Jun; Pirooznia, Mehdi; Corcoran, Philip C.; Thomas, Marvin L.; Lewis, Billeta G.T.; Jang, Moon Kyoo; Ayares, David L.; Horvath, Keith A.; Mohiuddin, Muhammad M.; Valantine, Hannah.

In: Journal of Heart and Lung Transplantation, 01.01.2018.

Research output: Contribution to journalArticle

Agbor-Enoh, S, Chan, JL, Singh, A, Tunc, I, Gorham, S, Zhu, J, Pirooznia, M, Corcoran, PC, Thomas, ML, Lewis, BGT, Jang, MK, Ayares, DL, Horvath, KA, Mohiuddin, MM & Valantine, H 2018, 'Circulating cell-free DNA as a biomarker of tissue injury: Assessment in a cardiac xenotransplantation model', Journal of Heart and Lung Transplantation. https://doi.org/10.1016/j.healun.2018.04.009
Agbor-Enoh, Sean ; Chan, Joshua L. ; Singh, Avneesh ; Tunc, Ilker ; Gorham, Sasha ; Zhu, Jun ; Pirooznia, Mehdi ; Corcoran, Philip C. ; Thomas, Marvin L. ; Lewis, Billeta G.T. ; Jang, Moon Kyoo ; Ayares, David L. ; Horvath, Keith A. ; Mohiuddin, Muhammad M. ; Valantine, Hannah. / Circulating cell-free DNA as a biomarker of tissue injury : Assessment in a cardiac xenotransplantation model. In: Journal of Heart and Lung Transplantation. 2018.
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abstract = "Background: Observational studies suggest that cell‐free DNA (cfDNA) is a biomarker of tissue injury in a range of conditions including organ transplantation. However, the lack of model systems to study cfDNA and its relevance to tissue injury has limited the advancements in this field. We hypothesized that the predictable course of acute humoral xenograft rejection (AHXR) in organ transplants from genetically engineered donors provides an ideal system for assessing circulating cfDNA as a marker of tissue injury. Methods: Heterotopic heart xenotransplantation was pre-transplantation on baboons (n = 7) using genetically modified pig donor hearts. Plasma cfDNA pre-transplant and at serial times post‐transplantation (n = 75) were shotgun sequenced. After alignment of sequence reads to pig and baboon reference sequences, we computed the percentage of xenograft-derived cfDNA (xdcfDNA) relative to recipient by counting uniquely aligned pig and baboon sequence reads. Results: The xdcfDNA percentage was high early post-transplantation and decayed exponentially to low stable levels (baseline); the decay half-life was 3.0 days. Post-transplantation baseline xdcfDNA levels were higher for transplant recipients that subsequently developed graft loss than in the 1 animal that did not reject the graft (3.2{\%} vs 0.5{\%}). Elevations in xdcfDNA percentage coincided with increased troponin and clinical evidence of rejection. Importantly, elevations in xdcfDNA percentage preceded clinical signs of rejection or increases in troponin levels. Conclusion: Cross‐species xdcfDNA kinetics in relation to acute rejection are similar to the patterns in human allografts. These observations in a xenotransplantation model support the body of evidence suggesting that circulating cfDNA is a marker of tissue injury.",
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T2 - Assessment in a cardiac xenotransplantation model

AU - Agbor-Enoh, Sean

AU - Chan, Joshua L.

AU - Singh, Avneesh

AU - Tunc, Ilker

AU - Gorham, Sasha

AU - Zhu, Jun

AU - Pirooznia, Mehdi

AU - Corcoran, Philip C.

AU - Thomas, Marvin L.

AU - Lewis, Billeta G.T.

AU - Jang, Moon Kyoo

AU - Ayares, David L.

AU - Horvath, Keith A.

AU - Mohiuddin, Muhammad M.

AU - Valantine, Hannah

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Background: Observational studies suggest that cell‐free DNA (cfDNA) is a biomarker of tissue injury in a range of conditions including organ transplantation. However, the lack of model systems to study cfDNA and its relevance to tissue injury has limited the advancements in this field. We hypothesized that the predictable course of acute humoral xenograft rejection (AHXR) in organ transplants from genetically engineered donors provides an ideal system for assessing circulating cfDNA as a marker of tissue injury. Methods: Heterotopic heart xenotransplantation was pre-transplantation on baboons (n = 7) using genetically modified pig donor hearts. Plasma cfDNA pre-transplant and at serial times post‐transplantation (n = 75) were shotgun sequenced. After alignment of sequence reads to pig and baboon reference sequences, we computed the percentage of xenograft-derived cfDNA (xdcfDNA) relative to recipient by counting uniquely aligned pig and baboon sequence reads. Results: The xdcfDNA percentage was high early post-transplantation and decayed exponentially to low stable levels (baseline); the decay half-life was 3.0 days. Post-transplantation baseline xdcfDNA levels were higher for transplant recipients that subsequently developed graft loss than in the 1 animal that did not reject the graft (3.2% vs 0.5%). Elevations in xdcfDNA percentage coincided with increased troponin and clinical evidence of rejection. Importantly, elevations in xdcfDNA percentage preceded clinical signs of rejection or increases in troponin levels. Conclusion: Cross‐species xdcfDNA kinetics in relation to acute rejection are similar to the patterns in human allografts. These observations in a xenotransplantation model support the body of evidence suggesting that circulating cfDNA is a marker of tissue injury.

AB - Background: Observational studies suggest that cell‐free DNA (cfDNA) is a biomarker of tissue injury in a range of conditions including organ transplantation. However, the lack of model systems to study cfDNA and its relevance to tissue injury has limited the advancements in this field. We hypothesized that the predictable course of acute humoral xenograft rejection (AHXR) in organ transplants from genetically engineered donors provides an ideal system for assessing circulating cfDNA as a marker of tissue injury. Methods: Heterotopic heart xenotransplantation was pre-transplantation on baboons (n = 7) using genetically modified pig donor hearts. Plasma cfDNA pre-transplant and at serial times post‐transplantation (n = 75) were shotgun sequenced. After alignment of sequence reads to pig and baboon reference sequences, we computed the percentage of xenograft-derived cfDNA (xdcfDNA) relative to recipient by counting uniquely aligned pig and baboon sequence reads. Results: The xdcfDNA percentage was high early post-transplantation and decayed exponentially to low stable levels (baseline); the decay half-life was 3.0 days. Post-transplantation baseline xdcfDNA levels were higher for transplant recipients that subsequently developed graft loss than in the 1 animal that did not reject the graft (3.2% vs 0.5%). Elevations in xdcfDNA percentage coincided with increased troponin and clinical evidence of rejection. Importantly, elevations in xdcfDNA percentage preceded clinical signs of rejection or increases in troponin levels. Conclusion: Cross‐species xdcfDNA kinetics in relation to acute rejection are similar to the patterns in human allografts. These observations in a xenotransplantation model support the body of evidence suggesting that circulating cfDNA is a marker of tissue injury.

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KW - genetically engineered donors

KW - tissue injury

KW - xenotransplantation

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