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Hinrichs, Arne; Riedel, Evamaria O.; Klymiuk, Nikolai; Blutke, Andreas; Kemter, Elisabeth; Laengin, Matthias; Dahlhoff, Maik; Kessler, Barbara; Kurome, Mayuko; Zakhartchenko, Valeri; Jemiller, Eva-Maria; Ayares, David; Bidlingmaier, Martin; Flenkenthaler, Florian; Hrabe de Angelis, Martin; Arnold, Georg J.; Reichart, Bruno; Fröhlich, Thomas and Wolf, Eckhard (2020): Growth hormone receptor knockout to reduce the size of donor pigs for preclinical xenotransplantation studies. In: Xenotransplantation, Vol. 28, No. 2, e12664

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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 alpha 1,3-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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