The potential of stem cells in the treatment of neonatal hypoxic-ischemic encephalopathy
DOI:
https://doi.org/10.15574/SP.2025.3(147).8796Keywords:
infants, encephalopathy, neurogenesis, stem cells, neuroprotection, mesenchymal cellsAbstract
Aim - to investigate the potential of stem cells in the treatment of neonatal encephalopathy, focusing on a systematic review of current scientific sources.
The review included articles published from 2010 to 2024, which highlight the effectiveness and safety of mesenchymal, induced pluripotent and neural stem cells in the treatment of hypoxic-ischemic encephalopathy. The PRISMA methodology ensured transparency and replicability of the analysis. The results confirm the high effectiveness of mesenchymal stem cells, which demonstrate anti-inflammatory, immunomodulatory properties and promote neurogenesis. Induced pluripotent cells are promising due to their ability to multilineage differentiation, although their use is limited by ethical aspects. The choice of the method of cell administration significantly affects the results: intravenous administration is safe but less precise, intracerebroventricular provides maximum effectiveness, while the intranasal method is becoming popular due to the possibility of avoiding systemic complications.
Stem cell therapy combined with hypothermia has shown a synergistic effect, opening new prospects for the treatment of neurodegenerative diseases.
The authors declare the absence of a conflict of interest.
References
Aboul-Soud MA, Alzahrani AJ, Mahmoud A. (2021). Induced pluripotent stem cells (iPSCs)-roles in regenerative therapies, disease modelling and drug screening. Cells. 10(9): 2319. https://doi.org/10.3390/cells10092319; PMid:34571968 PMCid:PMC8467501
Cecerska-Heryć E, Pękała M, Serwin N, Gliźniewicz M, Grygorcewicz B, Michalczyk A et al. (2023). The Use of Stem Cells as a Potential Treatment Method for Selected Neurodegenerative Diseases: Review. Cell Mol Neurobiol. 43(6): 2643-2673. https://doi.org/10.1007/s10571-023-01344-6; PMid:37027074 PMCid:PMC10333383
Chau MJ, Deveau TC, Song M, Gu X, Chen D, Wei L. (2014). iPSC Transplantation increases regeneration and functional recovery after ischemic stroke in neonatal rats. Stem Cells (Dayton, Ohio). 32(12): 3075-3087. https://doi.org/10.1002/stem.1802; PMid:25132189
Chehelgerdi M, Behdarvand Dehkordi F, Chehelgerdi M, Kabiri H Salehian-Dehkordi H, Abdolvand M et al. (2023). Exploring the promising potential of induced pluripotent stem cells in cancer research and therapy. Mol Cancer. 22(1): 189. https://doi.org/10.1186/s12943-023-01873-0; PMid:38017433 PMCid:PMC10683363
Chehelgerdi M, Chehelgerdi M, Khorramian-Ghahfarokhi M, Shafieizadeh M, Mahmoudi E, Eskandari F et al. (2024). Comprehensive review of CRISPR-based gene editing: mechanisms, challenges, and applications in cancer therapy. Mol Cancer. 23(1): 9. https://doi.org/10.1186/s12943-023-01925-5; PMid:38195537 PMCid:PMC10775503
Chen W, Lv L, Chen N, Cui E. (2023). Immunogenicity of mesenchymal stromal/stem cells. Scand J Immunol. 97(6): e13267. https://doi.org/10.1111/sji.13267; PMid:39007962
Chen X, Du J, Yun S, Xue C, Yao Y, Rao S. (2024). Recent advances in CRISPR-Cas9-based genome insertion technologies. Mol Ther Nucleic Acids. 35(1): 102138. https://doi.org/10.1016/j.omtn.2024.102138; PMid:38379727 PMCid:PMC10878794
Chen Y, Qu B, Zheng K, Liu Y, Lu L, Zhang X. (2024). Global research landscape and trends of cancer stem cells from 1997 to 2023: A bibliometric analysis. Medicine. 103(20): e38125. https://doi.org/10.1097/MD.0000000000038125; PMid:38758889 PMCid:PMC11098227
Déjosez M, Marin A, Hughes GM, Morales AE, Godoy-Parejo C, Gray JL et al. (2023). Bat pluripotent stem cells reveal unusual entanglement between host and viruses. Cell. 186(5): 957-974.e28. https://doi.org/10.1016/j.cell.2023.01.011; PMid:36812912 PMCid:PMC10085545
Du X, Kong D, Guo R, Liu B, He J, Zhang J et al. (2024). Combined transplantation of hiPSC-NSC and hMSC ameliorated neuroinflammation and promoted neuroregeneration in acute spinal cord injury. Stem Cell Res Ther. 15(1): 67. https://doi.org/10.1186/s13287-024-03655-x; PMid:38444003 PMCid:PMC10916262
Edoigiawerie S, Henry J, Issa N, David H. (2024). A systematic review of EEG and MRI features for predicting long-term neurological outcomes in cooled neonates with hypoxic-ischemic encephalopathy (HIE). Cureus. 16(10): e71431. https://doi.org/10.7759/cureus.71431; PMid:39539899 PMCid:PMC11558949
El Khatib MM, Ohmine S, Jacobus EJ, Tonne JM, Morsy SG, Holditch SJ et al. (2016). Tumor-Free Transplantation of Patient-Derived Induced Pluripotent Stem Cell Progeny for Customized Islet Regeneration. Stem Cells Transl Med. 5(5): 694-702. https://doi.org/10.5966/sctm.2015-0017; PMid:26987352 PMCid:PMC4835241
Elsman EB, Baba A, Offringa M, PRISMA-COSMIN Steering Committee. (2024). PRISMA-COSMIN 2024: New guidance aimed to enhance the reporting quality of systematic reviews of outcome measurement instruments. Int J Nurs Stud. 160: 104880. https://doi.org/10.1016/j.ijnurstu.2024.104880; PMid:39276710
Fan XL, Zhang Y, Li X, Fu QL. (2020). Mechanisms underlying the protective effects of mesenchymal stem cell-based therapy. Cell Mol Life Sci. 77(14): 2771-2794. https://doi.org/10.1007/s00018-020-03454-6; PMid:31965214 PMCid:PMC7223321
Fuchs E, Blau HM. (2020). Tissue stem cells: architects of their niches. Cell Stem Cell. 27(4): 532-556. https://doi.org/10.1016/j.stem.2020.09.011; PMid:33007238 PMCid:PMC7861346
Gänger S, Schindowski K. (2018). Tailoring formulations for intranasal nose-to-brain delivery: a review on architecture, physico-chemical characteristics and mucociliary clearance of the nasal olfactory mucosa. Pharmaceutics. 10(3): 116. https://doi.org/10.3390/pharmaceutics10030116; PMid:30081536 PMCid:PMC6161189
Guo Q, Zhai Q, Ji P. (2024). The Role of Mitochondrial Homeostasis in Mesenchymal Stem Cell Therapy-Potential Implications in the Treatment of Osteogenesis Imperfecta. Pharmaceuticals (Basel). 17(10): 1297. https://doi.org/10.3390/ph17101297; PMid:39458939 PMCid:PMC11510265
Han Y, Li X, Zhang Y, Han Y, Chang F, Ding J. (2019). Mesenchymal stem cells for regenerative medicine. Cells. 8(8): 886. https://doi.org/10.3390/cells8080886; PMid:31412678 PMCid:PMC6721852
Holvoet B, De Waele L, Quattrocelli M, Gheysens O, Sampaolesi M, Verfaillie CM et al. (2016). Increased Understanding of Stem Cell Behavior in Neurodegenerative and Neuromuscular Disorders by Use of Noninvasive Cell Imaging. Stem Cells Int. 2016: 6235687. https://doi.org/10.1155/2016/6235687; PMid:26997958 PMCid:PMC4779824
Isaković J, Šerer K, Barišić B, Mitrečić D. (2023). Mesenchymal stem cell therapy for neurological disorders: The light or the dark side of the force?. Front Bioeng Biotechnol. 11:1139359. https://doi.org/10.3389/fbioe.2023.1139359; PMid:36926687 PMCid:PMC10011535
Kharbikar BN, Mohindra P, Desai TA. (2022). Biomaterials to enhance stem cell transplantation. Cell Stem Cell. 29(5): 692-721. https://doi.org/10.1016/j.stem.2022.04.002; PMid:35483364 PMCid:PMC10169090
Kumar V, Vashishta M, Kong L, Wu X, Lu JJ, Guha C, Dwarakanath BS. (2021). The role of Notch, Hedgehog, and Wnt signaling pathways in the resistance of tumors to anticancer therapies. Front Cell Dev Biol. 9: 650772. https://doi.org/10.3389/fcell.2021.650772; PMid:33968932 PMCid:PMC8100510
Li F, Zhang K, Liu H, Yang T, Xiao DJ, Wang YS. (2020). The neuroprotective effect of mesenchymal stem cells is mediated through inhibition of apoptosis in hypoxic ischemic injury. World J Pediatr. 16(2):193-200. https://doi.org/10.1007/s12519-019-00310-x; PMid:31535281
Li Y, Wu H, Jiang X, Dong Y, Zheng J, Gao J. (2022). New idea to promote the clinical applications of stem cells or their extracellular vesicles in central nervous system disorders: combining with intranasal delivery. Acta Pharm Sin B. 12(8): 3215-3232. https://doi.org/10.1016/j.apsb.2022.04.001; PMid:35967290 PMCid:PMC9366301
Llorente V, Velarde P, Desco M, Gómez-Gaviro MV. (2022). Current understanding of the neural stem cell niches. Cells. 11(19): 3002. https://doi.org/10.3390/cells11193002; PMid:36230964 PMCid:PMC9563325
Maeda Y, Otsuka T, Takeda M, Okazaki T, Shimizu K, Kuwabara M et al. (2021). Transplantation of rat cranial bone-derived mesenchymal stem cells promotes functional recovery in rats with spinal cord injury. Sci Rep. 11(1): 21907. https://doi.org/10.1038/s41598-021-01490-1; PMid:34754046 PMCid:PMC8578570
Maric DM, Velikic G, Maric DL, Supic G, Vojvodic D, Petric V et al. (2022). Stem cell homing in intrathecal applications and inspirations for improvement paths. Int J Mol Sci. 23(8): 4290. https://doi.org/10.3390/ijms23084290; PMid:35457107 PMCid:PMC9027729
Mitsialis SA, Kourembanas S. (2016). Stem cell-based therapies for the newborn lung and brain: possibilities and challenges. Semin Perinatol. 40(3): 138-151. https://doi.org/10.1053/j.semperi.2015.12.002; PMid:26778234 PMCid:PMC4808378
Mousaei Ghasroldasht M, Seok J, Park HS, Liakath Ali FB, Al-Hendy A. (2022). Stem cell therapy: From idea to clinical practice. Int J Mol Sci. 23(5): 2850. https://doi.org/10.3390/ijms23052850; PMid:35269990 PMCid:PMC8911494
Ortuño-Costela MDC, Cerrada V, García-López M, Gallardo ME. (2019). The Challenge of Bringing iPSCs to the Patient. Int J Mol Sci. 20(24): 6305. https://doi.org/10.3390/ijms20246305; PMid:31847153 PMCid:PMC6940848
Ottoboni L, von Wunster B, Martino G. (2020). Therapeutic plasticity of neural stem cells. Front Neurol. 11: 148. https://doi.org/10.3389/fneur.2020.00148; PMid:32265815 PMCid:PMC7100551
Picerno A, Stasi A, Franzin R, Curci C, di Bari I, Gesualdo L et al. (2021). Why stem/progenitor cells lose their regenerative potential. World J Stem Cells. 13(11): 1714-1732. https://doi.org/10.4252/wjsc.v13.i11.1714; PMid:34909119 PMCid:PMC8641024
Qian K, Xu TY, Wang X, Ma T, Zhang KX, Yang K et al. (2020). Effects of neural stem cell transplantation on the motor function of rats with contusion spinal cord injuries: a meta-analysis. Neural Regen Res. 15(4): 748-758. https://doi.org/10.4103/1673-5374.266915; PMid:31638100 PMCid:PMC6975148
Qin D. (2019). Next-generation sequencing and its clinical application. Cancer Biol Med. 16(1): 4-10. https://doi.org/10.20892/j.issn.2095-3941.2018.0055; PMid:31119042 PMCid:PMC6528456
Rahimi Darehbagh R, Seyedoshohadaei SA, Ramezani R, Rezaei N. (2024). Stem cell therapies for neurological disorders: current progress, challenges, and future perspectives. Eur J Med Res. 29(1): 386. https://doi.org/10.1186/s40001-024-01987-1; PMid:39054501 PMCid:PMC11270957
Shahror RA, Linares GR, Wang Y, Hsueh SC, Wu CC, Chuang DM et al. (2020). Transplantation of mesenchymal stem cells overexpressing fibroblast growth factor 21 facilitates cognitive recovery and enhances neurogenesis in a mouse model of traumatic brain injury. J Neurotrauma. 37(1): 14-26. https://doi.org/10.1089/neu.2019.6422; PMid:31298621 PMCid:PMC6921331
Shaligram R, Garud BP, Malwade S, Mane SV, Dua J, Bahal M et al. (2024). Risk factors and predictors of outcomes in hypoxic-ischemic encephalopathy in neonates. Cureus. 16(11): e73407. https://doi.org/10.7759/cureus.73407
She HQ, Sun YF, Chen L, Xiao QX, Luo BY, Zhou HS et al. (2023). Current analysis of hypoxic-ischemic encephalopathy research issues and future treatment modalities. Front Neurosci. 17: 1136500. https://doi.org/10.3389/fnins.2023.1136500; PMid:37360183 PMCid:PMC10288156
Shoemaker LD, Kornblum HI. (2016). Neural stem cells (NSCs) and proteomics. Mol Cell Proteomics. 15(2): 344-354. https://doi.org/10.1074/mcp.O115.052704; PMid:26494823 PMCid:PMC4739658
Siddiqi F, Wolfe JH. (2016). Stem cell therapy for the central nervous system in lysosomal storage diseases. Hum Gene Ther. 27(10): 749-757. https://doi.org/10.1089/hum.2016.088; PMid:27420186 PMCid:PMC5035913
Tan F, Li X, Wang Z, Li J, Shahzad K, Zheng J. (2024). Clinical applications of stem cell-derived exosomes. Signal Transduct Target Ther. 9(1): 17. https://doi.org/10.1038/s41392-023-01704-0; PMid:38212307 PMCid:PMC10784577
Tesiye MR, Gol M, Fadardi MR, Kani SNM, Costa AM, Ghasemi-Kasman M et al. (2022). Therapeutic Potential of Mesenchymal Stem Cells in the Treatment of Epilepsy and Their Interaction with Antiseizure Medications. Cells. 11(24): 4129. https://doi.org/10.3390/cells11244129; PMid:36552892 PMCid:PMC9777461
Tetorou K, Sisa C, Iqbal A, Dhillon K, Hristova M. (2021). Current therapies for neonatal hypoxic-ischaemic and infection-sensitised hypoxic-ischaemic brain damage. Front Synaptic Neurosci. 13: 709301. https://doi.org/10.3389/fnsyn.2021.709301; PMid:34504417 PMCid:PMC8421799
Vining KH, Mooney DJ. (2017). Mechanical forces direct stem cell behaviour in development and regeneration. Nat Rev Mol Cell Biol. 18(12): 728-742. https://doi.org/10.1038/nrm.2017.108; PMid:29115301 PMCid:PMC5803560
Volarevic V, Markovic BS, Gazdic M, Volarevic A, Jovicic N, Arsenijevic N et al. (2018). Ethical and safety issues of stem cell-based therapy. Int J Med Sci. 15(1): 36-45. https://doi.org/10.7150/ijms.21666; PMid:29333086 PMCid:PMC5765738
Wang D, Zhang J. (2015). Effects of hypothermia combined with neural stem cell transplantation on recovery of neurological function in rats with spinal cord injury. Mol Med Rep. 11(3): 1759-1767. https://doi.org/10.3892/mmr.2014.2905; PMid:25385306 PMCid:PMC4270334
Yari H, Mikhailova MV, Mardasi M, Jafarzadehgharehziaaddin M, Shahrokh S, Thangavelu L et al. (2022). Emerging role of mesenchymal stromal cells (MSCs)-derived exosome in neurodegeneration-associated conditions: a groundbreaking cell-free approach. Stem Cell Res Ther. 13(1): 423. https://doi.org/10.1186/s13287-022-03122-5; PMid:35986375 PMCid:PMC9389725
Zakrzewski W, Dobrzyński M, Szymonowicz M, Rybak Z. (2019). Stem cells: past, present, and future. Stem Cell Res Ther. 10(1): 68. https://doi.org/10.1186/s13287-019-1165-5; PMid:30808416 PMCid:PMC6390367
Zhang R, Liu Y, Yan K, Chen L, Chen XR, Li P et al. (2013). Anti-inflammatory and immunomodulatory mechanisms of mesenchymal stem cell transplantation in experimental traumatic brain injury. J Neuroinflammation. 10: 106. https://doi.org/10.1186/1742-2094-10-106; PMid:23971414 PMCid:PMC3765323
Zhang X, Xue M, Liu A, Qiu H, Guo F. (2023). Activation of Wnt/β-catenin p130/E2F4 promotes the differentiation of bone marrow-derived mesenchymal stem cells into type II alveolar epithelial cells through cell cycle arrest. Exp Ther Med. 26(1): 330. https://doi.org/10.3892/etm.2023.12029; PMid:37346406 PMCid:PMC10280314
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