Neural progenitor cell transplantation results in structural and functional recovery in a rat model of cerebral palsy

Document Type : Original Article

Authors

1 Department of Cellular and Molecular Biology, Faculty of Advanced Sciences and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran

2 Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran

3 Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, Minnesota, United States

4 Department of Stem Cell and Developmental Biology, Cell Science Research Center, ROYAN Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran

5 Department of Brain and Cognitive Sciences, Cell Science Research Center, ROYAN Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran

10.22038/ijbms.2025.85616.18508

Abstract

Objective(s): Cerebral palsy (CP) is the most prevalent pediatric neurodevelopmental disorder. Stem cell therapy is a promising way to treat brain disorders, including CP. This study sought to establish a model using pregnant rats to induce CP similarly to that observed in humans. This approach aims to enhance our understanding of the mechanisms underlying CP and explores the potential for healing brain injuries through the transplantation of neural progenitor cells (NPCs).
Materials and Methods: In this experimental study, stress conditions were induced to create a CP model in neonatal rats. Initially, the uterine vein was blocked in pregnant rats to induce hypoxic conditions. Consequently, histological analyses are performed to assess the extent of brain damage in rats. 
Results: The findings indicated that the CP group exhibited notable pathological alterations, as shown by histochemical analysis, which revealed lesions in the cortical brain tissues of neonatal rats. After confirming our CP model, NPCs were transplanted into the motor cortex of CP neonates (PND7) by microinjection. After two days, the neonates were sacrificed, and the brain tissue was pathologically analyzed. Our study shows that transplantation of neural progenitor cells decreases inflammation and regulation of astrogenesis.
Conclusion: The induction of hypoxia-ischemia (HI) in the uterus appears to be a reliable animal model for studying CP mechanisms. Additionally, our research demonstrates that the transplantation of NPCs is a promising therapeutic approach for treating CP. This advancement will enhance our comprehension and aid in the refinement of cellular therapeutic strategies.

Keywords

Main Subjects

References

1. Paneth N. Establishing the diagnosis of cerebral palsy. Clin Obstet Gynecol 2008; 51:742-748. 
2. Kakooza-Mwesige A, Andrews C, Peterson S, Mangen FW, Eliasson AC, Forssberg H. Prevalence of cerebral palsy in Uganda: A population-based study. Lancet Glob Health 2017; 5:1275-1282. 
3. Patel DR, Neelakantan M, Pandher K, Merrick J. Cerebral palsy in children: A clinical overview. Transl Pediatr 2020; 9:125-135.
4. Haramshahi M, Toopchizadeh V, Pourzeinali S, Nikkhesal N, Sefidi Heris T, Farshbaf-Khalili A, et al. Cerebral palsy: Potential risk factors and functional status among children under three years, a case-control study in northwest Iran. BMC Pediatrics 2024; 24:695-705.
5. Rosenbaum P, Paneth N, Leviton A, Goldstein M, Bax M, Damiano D, et al. A report: The definition and classification of cerebral palsy. Dev Med Child Neurol Suppl 2007; 109:8-14.
6. Gulati S, Sondhi V. Cerebral palsy: An overview. Indian J Pediatr 2018; 85:1006-1016.
7. Monono N, Oumarou A, Cyrille N, Sissi V. Prevalence and parental psychological burden of cerebral palsy in the paediatric population consulting at the buea and limbe regional hospitals. Pediatr Neonatol 2024; 6: 1-13. 
8. Salomon I. Neurobiological insights into cerebral palsy: A review of the mechanisms and therapeutic strategies. Brain Behav 2024; 14:70065.
9. Andreani JCM, Guma C. New animal model to mimic spastic cerebral palsy: The brain‐damaged pig preparation. Neuromodulation 2008; 11:196-201.
10. Johnston MV, Ferriero DM, Vannucci SJ, Hagberg H. Models of cerebral palsy: Which ones are best?. J Child Neurol 2008; 20:984-987.
11. Baburamani A, Ek CJ, Walker DW, Castillo-Melendez M. Vulnerability of the developing brain to hypoxic-ischemic damage: Contribution of the cerebral vasculature to injury and repair?. Front Physiol 2012; 3:424-444.
12. Khot S, Tirschwell DL. Long-term neurological complications after hypoxic-ischemic encephalopathy. Semin Neurol 2006; 26:422-431.
13. Back SA, Rivkees SA. Emerging concepts in periventricular white matter injury. Semin Perinatol 2004; 28:405-414.
14. Zaghloul N , Patel H, Nagy Ahmed M. A model of Periventricular Leukomalacia (PVL) in neonate mice with histopathological and neurodevelopmental outcomes mimicking human PVL in neonates. PLoS One  2017; 12:0175438.
15. Santa-Cecília FV, Socias B, Ouidja MO, Sepulveda-Diaz JE, Acuna L, Silva RL, et al. Doxycycline suppresses microglial activation by inhibiting the p38 MAPK and NF-kB signaling pathways. Neurotox Res 2016; 29:447-459.
16. Rumajogee P, Bregman T, Miller SP, Yager JY, Fehlings MG. Rodent hypoxia–ischemia models for cerebral palsy research: A systematic review. Front Neurol 2016; 7:57-76. 
17. Schuch CP, Diaz R, Deckmann I, Rojas JJ, Deniz BF, Pereira LO. Early environmental enrichment affects neurobehavioral development and prevents brain damage in rats submitted to neonatal hypoxia-ischemia. Neurosci Lett 2016; 617:101-107.
18. Kannan S, Dai H, Navath RS, Balakrishnan B, Jyoti A, Janisse J, et al. Dendrimer-based postnatal therapy for neuroinflammation and cerebral palsy in a rabbit model. Sci Transl Med 2012; 4:130-146. 
19. Hamdy N, Eide S, Sun H, Feng Z. Animal models for neonatal brain injury induced by hypoxic ischemic conditions in rodents. Exp Neurol 2020; 334:113457. 
20. Feather-Schussler DN, Ferguson TS. A battery of motor tests in a neonatal mouse model of cerebral palsy. J Vis Exp 2016; 117:53569-53580.
21. Reis C, Wilkinson M, Reis H, Akyol O, Gospodarev V, Araujo C, et al. A Look into Stem Cell Therapy: Exploring the Options for Treatment of Ischemic Stroke. Stem Cells Int 2017; 2017:3267352.
22. Liu, Z, Li P, Zhao D, Tang H, Goa J. Protective effect of extract of Cordyceps sinensis in middle cerebral artery occlusion-induced focal cerebral ischemia in rats. Behav Brain Funct 2010; 6:1-6.
23. Biernaskie J, Corbett D. Enriched rehabilitative training promotes improved forelimb motor function and enhanced dendritic growth after focal ischemic injury. J Neurosci 2001; 21:5272-5280.
24. Xiong M, Ma S, Shao X, Yang Y, Zhou W. Hypoxic ischaemic hypothermia promotes neuronal differentiation and inhibits glial differentiation from newly generated cells in the SGZ of the neonatal rat brain. Neurosci Lett 2012; 523:87-92.
25. Ji X, Ma L, Zhou W, Xiong M. Narrative review of stem cell therapy for ischemic brain injury. Transl Pediatr 2021; 10:435-445.
26. Li Y, Chen J, Chen X, Wang L, Gautam S, Xu Y, et al. Human marrow stromal cell therapy for stroke in rat: Neurotrophins and functional recovery. Neurology 2002; 59:514-523.
27. Ryu S, Lee S, Kim S, Yoon B. Human neural stem cells promote proliferation of endogenous neural stem cells and enhance angiogenesis in ischemic rat brain. Neural Regen Res 2016; 11:298-304.
28. Zhao L, Liu JW, Shi HY, Ma YM. Neural stem cell therapy for brain disease. World J Stem Cells 2021; 13:1278-1292.
29. Jiao Y, Li XY, Liu J. A new approach to cerebral palsy treatment: Discussion of the effective components of umbilical cord blood and its mechanisms of sction. Cell Transplant 2019; 28:497-509.
30. Ramyar Rahimi R, Seyedoshohadaei S, Ramezani R, Rezaei N. Stem cell therapies for neurological disorders: current progress, challenges and future perspectives. Eur J Med Res 2024; 29:386-408.
31. Xiang A, Fu Y, Wang Ch, Huang D, Qi J, Zhao R, et al. Aquatic therapy for spastic cerebral palsy: A scoping review. Eur J Med Res 2024; 29:569-584.
32. Boyalı O, Kabatas S, Civelek E, Ozdemir O, Bahar-Ozdemir Y, Kaplan N. Allogeneic mesenchymal stem cells may be a viable treatment modality in cerebral palsy. World J Clin Cases 2024; 12:1585-1596.
33. Tang Y, Yu P, Cheng L. Current progress in the derivation and therapeutic application of neural stem cells. Cell Death Dis 2017; 8:e3108.
34. Li F, Zhang K, Liu H, Yang T, Xiao D, Wang Y. The neuroprotective effect of mesenchymal stem cells is mediated through inhibition of poptosis in hypoxic ischemic injury. World J Pediatr 2020; 16:193-200.
35. Huang L,Wong S, Snyder E, Hamblin M, Lee J. Human neural stem cells rapidly ameliorate symptomatic inflammation in early-stage ischemic-reperfusion cerebral injury. Stem Cell Res Ther 2014; 5:1-16.
36. Homayouni Moghadam F, Sadeghi-Zadeh M, Alizadeh-Shoorjestan B, Dehghani-Varnamkhasti R, Narimani S, Darabi L, et al. Isolation and culture of embryonic mouse neural stem cells. J Vis Exp 2018; 141:58874. 
37. Kádár A, Wittmann G, Liposits Z, Fekete C. Improved method for combination of immunocytochemistry and Nissl staining. J Neurosci Methods 2009; 184:115-118.
38. Feldman AT, Wolfe D. Tissue processing and hematoxylin and eosin staining. Methods Mol Biol 2014; 1180:31-43.
39. Zaidi F. Gender differences in human brain: A review. Anat J 2010; 2:37-55.
40. Chew LJ, Fusar-Poli P, Schmitz T. Oligodendroglial alterations and the role of microglia in white matter injury: Relevance to schizophrenia. Dev Neurosci 2013; 35:102-129. 
41. Johnston MV, Ferriero DM, Vannucci SJ, Hagberg H. Models of cerebral palsy: Which ones are best?. J Child Neurol 2005; 20:984-987. 
42. Ment LR, Stewart WB, Duncan CC, Pitt BR, Cole J. Beagle puppy model of perinatal cerebral infarction: Regional cerebral prostaglandin changes during acute hypoxemia. J Neurosurg 1986; 65:851-855.
43. Jabarpour M, Siavashi V, Asadian S, Babaei H, Jafari SM, Nassiri SM. Hyper bilirubinemia-induced pro-angiogenic activity of infantile endothelial progenitor cells. Microvasc Res 2018; 118:49-56.
44. Leviton A, Allred EN, Kuban KC, Hecht JL, Onderdonk AB, O’shea TM, et al. Microbiologic and histologic characteristics of the extremely preterm infant’s placenta predict white matter damage and later cerebral palsy. the ELGAN study. Pediatr Res 2010; 67:95-101. 
45. Faulkner S, Ruff C, Fehlings M. The potential for stem cells in cerebral palsy piecing together the puzzle. Semin Pediatr Neurol 2013; 20:146-153.
46. Mao S, Xiong G, Zhang L, Dong H, Liu B, Cohen N, et al. Verification of the cross immunoreactivity of A60, a mouse monoclonal antibody against neuronal nuclear protein. Front Neuroanat 2016; 10:54-64.
47. Vitrikas K, Dalton H, Breish D. Cerebral palsy: An overview. Am Fam Physician 2020; 101:213-220.
48. Ito J, Araki A, Tanaka H, Tasaki T, Cho K, Yamazaki R. Muscle histopathology in spastic cerebral palsy. Brain Dev 1996; 18:299-303. 
49. Wadhwa P, Jain P, Jadhav HR, Glycogen synthase kinase 3 (GSK3): Its role and inhibitors. Curr Top Med Chem 2020; 20:1522-1534. 
Iranian Journal of Basic Medical Sciences
Volume 28, Issue 9
September 2025
Pages 1230-1241

Files

Share

How to cite

Statistics