The growth of xenotransplanted hearts can be reduced with growth hormone receptor knockout pig donors

Goerlich, Corbin E.; Griffith, Bartley P.; Hanna, Peter; Hong, Susie N.; Ayares, David; Singh, Avneesh K.; Mohiuddin, Muhammad M.

doi:10.1016/j.jtcvs.2021.07.051

Cited by 63 publications

(70 citation statements)

References 21 publications

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“…Chen et al also found an advantage in using GTKO pig kidneys over previously used transgenic kidneys ( 5 ). Recently, GTKO pigs along with other transgene have significantly improved the cardiac xenograft survivals in NHP to months in OHTx and years in HHTx models ( 14 , 15 , 69 , 70 ).…”

Section: Overcoming the Challenges For Successful Cardiac Xenotranspl...mentioning

confidence: 99%

“…However, multi-gene pigs with double and triple carbohydrate knockouts have been developed for cardiac xenotransplantation and are currently being tested in OHTx and HHTx models. Recently, we have achieved up to 264 day survival of a multi-gene cardiac xenograft with additional human transgene and knockouts ( 69 ). Notable modifications in these pigs were are carbohydrate enzyme KO (GTKO and β4GalNT2), growth hormone receptor knockout (GHRKO) and the addition of human transgenes (hCD46, hTBM, hEPCR and hCD47).…”

Section: Progress In Cardiac Xenotransplantation Toward Clinical Tran...mentioning

confidence: 99%

“…They demonstrate that GHRKO pigs have slow or reduced growth, including their organs’ growth, compared to normal wild-type pigs ( 61 , 104 – 107 ). Recently, Goerlich, et al have examined intrinsic and extrinsic causes of graft growth after transplantation in an OHTx model using “multi-gene” pigs growth hormone receptor knockout pigs (GHRKO) ( 69 ). Post-transplantation xenograft growth was measured by echocardiography longitudinally after transplantation between multi-gene cardiac xenografts with and without GHRKO.…”

Section: Overcoming the Challenges For Successful Cardiac Xenotranspl...mentioning

confidence: 99%

See 2 more Smart Citations

Cardiac Xenotransplantation: Progress in Preclinical Models and Prospects for Clinical Translation

Singh¹,

Goerlich²,

Shah³

et al. 2022

Transpl Int

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Survival of pig cardiac xenografts in a non-human primate (NHP) model has improved significantly over the last 4 years with the introduction of costimulation blockade based immunosuppression (IS) and genetically engineered (GE) pig donors. The longest survival of a cardiac xenograft in the heterotopic (HHTx) position was almost 3 years and only rejected when IS was stopped. Recent reports of cardiac xenograft survival in a life-sustaining orthotopic (OHTx) position for 6 months is a significant step forward. Despite these achievements, there are still several barriers to the clinical success of xenotransplantation (XTx). This includes the possible transmission of porcine pathogens with pig donors and continued xenograft growth after XTx. Both these concerns, and issues with additional incompatibilities, have been addressed recently with the genetic modification of pigs. This review discusses the spectrum of issues related to cardiac xenotransplantation, recent progress in preclinical models, and its feasibility for clinical translation.

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Section: Overcoming the Challenges For Successful Cardiac Xenotranspl...mentioning

confidence: 99%

Section: Progress In Cardiac Xenotransplantation Toward Clinical Tran...mentioning

confidence: 99%

Section: Overcoming the Challenges For Successful Cardiac Xenotranspl...mentioning

confidence: 99%

See 1 more Smart Citation

Cardiac Xenotransplantation: Progress in Preclinical Models and Prospects for Clinical Translation

Singh¹,

Goerlich²,

Shah³

et al. 2022

Transpl Int

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“…Our lab recently published synergistic findings in the context of growth hormone receptor knockout (GHRKO) pig hearts transplanted in baboon recipients, an upstream signaling receptor for insulin‐like growth factor‐1 (IGF‐1) 2 . Post‐transplantation cardiac xenograft hypertrophy has been observed within one month of transplantation, resulting in invariable life‐limiting diastolic heart failure 3 .…”

Section: Figurementioning

confidence: 99%

“…9 We demonstrated that the addition of GHRKO to these genetically engineered cardiac xenografts, in order to reduce xenograft growth, prolongs survival up to 9 months (264 days). 2 testing this hypothesis would be to compare wild-type and GHRKO knockout mice 10,11 under hypertensive states and observe whether there is differential cardiac hypertrophy and resident macrophage IGF-1 expression between the two groups. We commend the authors for a well-designed study and look forward to future work by this group.…”

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confidence: 99%

An intrinsic link to an extrinsic cause of cardiac xenograft growth after xenotransplantation

Goerlich

Singh

Treffalls

et al. 2022

Xenotransplantation

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Post‐transplantation cardiac xenograft growth in an orthotopic pig to baboon model is a life‐limiting phenomenon that is poorly understood. Possible causes of growth include both intrinsic and extrinsic etiologies. Extrinsic causes are thought to be attributed to maladaptive hypertrophy as a result of increased mean arterial pressure experienced by the cardiac xenograft after transplantation. Intrinsic causes are thought to be a result of discordant growth between pig xenografts and recipients. This results in intrinsic xenograft growth that parallels the donor and continues in a recipient in which growth is relatively minimal, controlled in part by the growth hormone receptor, IGF‐1 axis. Recently, Zaman, et al. published a study titled, “Selective loss of resident macrophage‐derived insulin‐like growth factor‐1 abolishes adaptive cardiac growth to stress,” in Immunity, Volume 54; Issue 9, pp. 2057–2071. They demonstrated that insulin growth factor‐secreting resident macrophages that sense hypertensive stress are a mechanistic link to hypertension and maladaptive hypertrophy in the setting of hypertension. While notable in its own right, we comment on how this work may shed light on a new underlying mechanism for the use of growth hormone receptor knockout (GHRKO) pig donors and its role in addressing post‐transplantation xenograft growth. We hypothesize that GHRKO pig donors contain syngeneic resident cardiac macrophages that abrogate IGF‐1 mediated maladaptive hypertrophy from hypertension. Futures studies in post‐transplantation cardiac xenotransplantation growth should examine this mechanism as a potential contributor.

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Heart and Lung Xenotransplantation

Jane,

Miller,

Madsen

2023

Textbook of Transplantation and Mechanical Support for End‐Stage Heart and Lung Disease

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The growth of xenotransplanted hearts can be reduced with growth hormone receptor knockout pig donors

Cited by 63 publications

References 21 publications

Cardiac Xenotransplantation: Progress in Preclinical Models and Prospects for Clinical Translation

Cardiac Xenotransplantation: Progress in Preclinical Models and Prospects for Clinical Translation

An intrinsic link to an extrinsic cause of cardiac xenograft growth after xenotransplantation

Heart and Lung Xenotransplantation

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