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Hinrichs, A.* ; Riedel, E.O.* ; Klymiuk, N.* ; Blutke, A. ; Kemter, E.* ; Längin, M.* ; Dahlhoff, M.* ; Keßler, B.* ; Kurome, M.* ; Zakhartchenko, V.* ; Jemiller, E.M.* ; Ayares, D.* ; Bidlingmaier, M.* ; Flenkenthaler, F.* ; Hrabě de Angelis, M.* ; Arnold, G.J.* ; Reichart, B.* ; Fröhlich, T.* ; Wolf, E.*

Growth hormone receptor knockout to reduce the size of donor pigs for preclinical xenotransplantation studies.

Xenotransplantation, DOI: 10.1111/xen.12664 (2020)
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Open Access Gold (Paid Option)
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Background: Many genetically multi-modified donor lines for xenotransplantation have a background of domestic pigs with rapid body and organ growth. The intrinsic growth potential of porcine xeno-organs may impair their long-term function after orthotopic transplantation in non-human primate models. Since growth hormone is a major stimulator of postnatal growth, we deleted its receptor (GHR-KO) to reduce the size of donor pigs in one step. Methods: Heart weight and proteome profile of myocardium were investigated in GHR-KO and control pigs. GHR-KO mutations were introduced using CRISPR/Cas9 in an α1,3-galactosyltransferase (GGTA1)-deficient background expressing the human cluster of differentiation (hCD46) and human thrombomodulin (hTHBD) to generate quadruple-modified (4GM) pigs. Results: At age 6 months, GHR-KO pigs had a 61% reduced body weight and a 63% reduced heart weight compared with controls. The mean minimal diameter of cardiomyocytes was 28% reduced. A holistic proteome study of myocardium samples from the two groups did not reveal prominent differences. Two 4GM founder sows had low serum insulin-like growth factor 1 (IGF1) levels (24 ± 1 ng/mL) and reached body weights of 70.3 and 73.4 kg at 9 months. Control pigs with IGF1 levels of 228 ± 24 ng/mL reached this weight range three months earlier. The 4GM sows showed normal sexual development and were mated with genetically multi-modified boars. Offspring revealed the expected Mendelian transmission of the genetic modifications and consistent expression of the transgenes. Conclusion: GHR-KO donor pigs can be used at an age beyond the steepest phase of their growth curve, potentially reducing the problem of xeno-organ overgrowth in preclinical studies.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Gene Editing ; Growth Hormone Receptor ; Organ Growth ; Pig; Gene; Expression; Rejection; Lessons; Graft
ISSN (print) / ISBN 0908-665X
e-ISSN 1399-3089
Publisher Wiley
Publishing Place Hoboken, NJ
Reviewing status Peer reviewed
Grants Deutsche Forschungsgemeinschaft