Severe-combined immunodeficient rats can be used to generate a model of perinatal hypoxic-ischemic brain injury to facilitate studies of engrafted human neural stem cells.

Publisher: Public Library of Science Country of Publication: United States NLM ID: 101285081 Publication Model: eCollection Cited Medium: Internet ISSN: 1932-6203 (Electronic) Linking ISSN: 19326203 NLM ISO Abbreviation: PLoS One Subsets: MEDLINE

Original Publication: San Francisco, CA : Public Library of Science

Disease Models, Animal*; Hypoxia-Ischemia, Brain/*therapy ; Induced Pluripotent Stem Cells/*transplantation ; Neural Stem Cells/*transplantation; Animals ; Animals, Newborn ; Brain/pathology ; Cell Survival ; DNA-Activated Protein Kinase/genetics ; Gliosis/pathology ; Gliosis/therapy ; Humans ; Hypoxia-Ischemia, Brain/genetics ; Hypoxia-Ischemia, Brain/pathology ; Induced Pluripotent Stem Cells/pathology ; Neural Stem Cells/pathology ; Nuclear Proteins/genetics ; Random Allocation ; Rats, Long-Evans ; Rats, Transgenic ; Severe Combined Immunodeficiency/genetics ; Transplantation, Heterologous

Cerebral palsy (CP) encompasses a group of non-progressive brain disorders that are often acquired through perinatal hypoxic-ischemic (HI) brain injury. Injury leads to a cascade of cell death events, resulting in lifetime motor and cognitive deficits. There are currently no treatments that can repair the resulting brain damage and improve functional outcomes. To date, preclinical research using neural precursor cell (NPC) transplantation as a therapy for HI brain injury has shown promise. To translate this treatment to the clinic, it is essential that human-derived NPCs also be tested in animal models, however, a major limitation is the high risk of xenograft rejection. A solution is to transplant the cells into immune-deficient rodents, but there are currently no models of HI brain injury established in such a cohort of animals. Here, we demonstrate that a model of HI brain injury can be generated in immune-deficient Prkdc knockout (KO) rats. Long-term deficits in sensorimotor function were similar between KO and wildtype (WT) rats. Interestingly, some aspects of the injury were more severe in KO rats. Additionally, human induced pluripotent stem cell derived (hiPSC)-NPCs had higher survival at 10 weeks post-transplant in KO rats when compared to their WT counterparts. This work establishes a reliable model of neonatal HI brain injury in Prkdc KO rats that will allow for future transplantation, survival, and long-term evaluation of the safety and efficacy of hiPSC-NPCs for neonatal brain damage. This model will enable critical preclinical translational research using human NPCs.
Competing Interests: The authors have declared that no competing interests exist.

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0 (Nuclear Proteins)
EC 2.7.11.1 (DNA-Activated Protein Kinase)
EC 2.7.11.1 (Prkdc protein, rat)

Date Created: 20181129 Date Completed: 20190501 Latest Revision: 20231004

20240105

PMC6261629

10.1371/journal.pone.0208105

30485360