Advances in prenatal screening and early diagnosis of genetic disease will potentially allow for preemptive treatment of anticipated postnatal disease by in utero cell transplantation (IUCT). This strategy carries potential benefits over postnatal treatment, which might allow for improved engraftment and function of the transplanted cells. Congenital metabolic disorders may be an ideal target for this type of therapy, as in most cases, they require replacement of a single deficient hepatic enzyme, and multiple small-animal models exist for preclinical testing.
The Gunn rat, a Crigler–Najjar syndrome model animal lacking UDP-glucuronosyltransferase (UGT1A1), was used as recipient. Human amniotic epithelial cells (hAECs), which possess hepatic differentiation potential, were transplanted into the midgestation fetal Gunn rat liver via ultrasound-guided IUCT. The impact of IUCT on live birth and postnatal survival was evaluated. Human cell engraftment was immunohistochemically analyzed on postnatal day 21.
Ultrasound-guided IUCT was conducted in rat fetuses on embryonic day 16. Following IUCT, the antihuman mitochondria-positive cells were detected in the liver of recipient rats at postnatal day 21.
Here, we have introduced ultrasound-guided IUCT of hAEC using a small-animal model of a congenital metabolic disorder without immunosuppression. The immunological advantage of IUCT was demonstrated with xenogeneic IUCT. This procedure is suitable to conduct preclinical studies for exploring the feasibility and efficacy of ultrasound-guided transuterine cell injection using rodent disease models.
1 Department of Obstetrics and Gynecology, Keck School of Medicine, University of Southern California, Los Angeles, CA.
2 Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA.
Received 16 December 2018. Revision received 27 February 2019.
Accepted 1 March 2019.
This work was supported by the Department of Obstetrics and Gynecology (BG, RC), Short-Term Research Experience for Underrepresented Persons (STEP-UP)/NIDDK/NIH Grant R25 DK 078385 (MC), and California Institute for Regenerative Medicine (CIRM) grant TR3-05488 (TM) and grant TB1-01176 (KP).
T.M. owns stock in Noveome Biotherapeutics, Inc. The other authors declare no conflicts of interest.
B.H.G. designed the studies, collected placentae, carried out the in utero cell injections, and prepared the article. M.M.C. contributed to the cell isolation and culture, maintenance of the Gunn rat colony, and in utero cell injections. K.R.P. conducted immunohistochemistry. R.H.C. participated in data interpretation and preparation of the article. T.M. participated in the design of the studies, data interpretation, and preparation of the article.
Correspondence: Brendan H. Grubbs, MD, MA, 1200 N. State St, IRD 220, Los Angeles, CA 90033. (Brendan.Grubbs@med.usc.edu).