Human neural progenitor cells ameliorate NMDA-induced hippocampal degeneration and related functional deficits

Sabrina K Uppal; Toni L Uhlendorf; Ruslan L Nuryyev; Jacqueline Saenz; Menaga Shanmugam; Jessica Ochoa; William Van Trigt; Cindy S Malone; Andrew P St. Julian; Oleg Kopyov; Alex Kopyov; Randy W Cohen; Sabrina K Uppal; Toni L Uhlendorf; Ruslan L Nuryyev; Jacqueline Saenz; Menaga Shanmugam; Jessica Ochoa; William Van Trigt; Cindy S Malone; Andrew P St. Julian; Oleg Kopyov; Alex Kopyov; Randy W Cohen

doi:10.3934/medsci.2021021

AIMS Medical Science

2021, Volume 8, Issue 3: 252-268. doi: 10.3934/medsci.2021021

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Human neural progenitor cells ameliorate NMDA-induced hippocampal degeneration and related functional deficits

1.
Department of Biology, California State University, Northridge, Northridge, CA 91330, USA
2.
Celavie Biosciences LLC, Oxnard, CA USA

Received: 15 April 2021 Accepted: 22 September 2021 Published: 28 September 2021

It has been established that the CA3 region of the hippocampus is involved in consolidating short-term memory to long-term memory and aids in spatial navigation retention. Seizures and many neurologic diseases induce damage to that region of the hippocampus, resulting in deficits in memory consolidation and spatial navigation. Drug treatments have been proven to have limited effectiveness, but cell replacement therapy has demonstrated to be more promising. Celavie Biosciences have developed a multipotent, nontumorigenic human neural progenitor cell (hNPC) line shown to have the ability to migrate in situ, reducing structural and functional deficits in neurodegenerative animal models. Here, we examined whether transplanted hNPCs would reestablish the memories of Han-Wistar rats subjected to hippocampal excitotoxic lesioning. The rats were lesioned in the CA3c regions at 50 days bilaterally with the neurotoxin NMDA (1 µl containing 7.5 mg/ml; −3.5 mm AP; ±2.0 L and −2.5 V). At 54 days of age, live hNPCs (500000 cells in 5 µl cell suspension media), frozen-killed hNPCs (500000 cells/5 µl), HEK293T cells (500000 cells/5 µl) or vehicle (cell suspension media; 5 µl) were bilaterally implanted directly into the NMDA damaged area. The rats were tested two weeks later with three different memory tests: novel and place-object assays and the water-maze task. Results showed that rats receiving live hNPC implantation performed significantly better in the water maze task than control groups; yet, novel and place-object test results showed no significant differences among treatments. Histology confirmed the survival of implanted hNPCs after 28 days post-implantation as well as showing neuroprotective effects. This study showed that Celavie's hNPCs were able to survive and improve some but not all hippocampal functionality, emphasizing the promise for cell replacement therapeutics for neurodegenerative disorders.
- CA3c region,
- replacement cell therapy,
- water maze,
- hippocampus,
- novel object test
Citation: Sabrina K Uppal, Toni L Uhlendorf, Ruslan L Nuryyev, Jacqueline Saenz, Menaga Shanmugam, Jessica Ochoa, William Van Trigt, Cindy S Malone, Andrew P St. Julian, Oleg Kopyov, Alex Kopyov, Randy W Cohen. Human neural progenitor cells ameliorate NMDA-induced hippocampal degeneration and related functional deficits[J]. AIMS Medical Science, 2021, 8(3): 252-268. doi: 10.3934/medsci.2021021

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Abstract

It has been established that the CA3 region of the hippocampus is involved in consolidating short-term memory to long-term memory and aids in spatial navigation retention. Seizures and many neurologic diseases induce damage to that region of the hippocampus, resulting in deficits in memory consolidation and spatial navigation. Drug treatments have been proven to have limited effectiveness, but cell replacement therapy has demonstrated to be more promising. Celavie Biosciences have developed a multipotent, nontumorigenic human neural progenitor cell (hNPC) line shown to have the ability to migrate in situ, reducing structural and functional deficits in neurodegenerative animal models. Here, we examined whether transplanted hNPCs would reestablish the memories of Han-Wistar rats subjected to hippocampal excitotoxic lesioning. The rats were lesioned in the CA3c regions at 50 days bilaterally with the neurotoxin NMDA (1 µl containing 7.5 mg/ml; −3.5 mm AP; ±2.0 L and −2.5 V). At 54 days of age, live hNPCs (500000 cells in 5 µl cell suspension media), frozen-killed hNPCs (500000 cells/5 µl), HEK293T cells (500000 cells/5 µl) or vehicle (cell suspension media; 5 µl) were bilaterally implanted directly into the NMDA damaged area. The rats were tested two weeks later with three different memory tests: novel and place-object assays and the water-maze task. Results showed that rats receiving live hNPC implantation performed significantly better in the water maze task than control groups; yet, novel and place-object test results showed no significant differences among treatments. Histology confirmed the survival of implanted hNPCs after 28 days post-implantation as well as showing neuroprotective effects. This study showed that Celavie's hNPCs were able to survive and improve some but not all hippocampal functionality, emphasizing the promise for cell replacement therapeutics for neurodegenerative disorders.

Abbreviations

DAB

Diaminobenzidine

hNPC

Human neural progenitor cell

IGF-1

Insulin-like growth factor-1

PBS

Phosphate buffer saline

PFA

Paraformaldehyde

SZD

Subventricular zone-derived

Acknowledgments

We would like to thank the vivarium staff for providing assistance and taking care of the animals. A special thanks to Dr. Lisa Banner for taking the time to review this study.

Conflict of interest

The authors declared no impending conflicts of interest with regard to this study, authorship, or publication of this article.

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