Lin Wei,Jiang Xian,Li Peng,et al.Stem cell transplantation via suppressing neuroinflammation for treating neonatal intraventricular hemorrhage[J].Journal of Clinical Pediatric Surgery,2026,(02):140-145.[doi:10.3760/cma.j.cn101785-20251029-00025]
干细胞移植抑制神经炎症治疗新生儿脑室内出血的研究进展
- Title:
- Stem cell transplantation via suppressing neuroinflammation for treating neonatal intraventricular hemorrhage
- Keywords:
- Cerebral Intraventricular Hemorrhage; Stem Cell Transplantation; Nerve; Inflammation; Infant; Newborn
- 摘要:
- 新生儿脑室内出血(intraventricular hemorrhage,IVH)是早产儿常见且严重的神经系统疾病,神经炎症反应是新生儿IVH后重要的病理生理过程,最终可导致继发性脑白质损伤和远期神经发育障碍。现行治疗仅限于脑积水分流与对症支持治疗,但无法阻断原发出血后神经炎症级联反应,也难以实现神经修复。近年来,干细胞及其外泌体因具有多向分化潜能、低免疫原性、旁分泌和免疫重编程等特性,成为IVH病因学干预的研究热点。然而,最佳细胞来源、细胞移植剂量、移植途径与时机尚未达成共识,其致瘤性风险及长期神经发育结局仍然需要大规模随机对照试验来验证。未来应整合多组学技术或联合治疗等策略,推动干细胞移植治疗从实验室走向临床,为IVH提供循证、安全、有效的病因学治疗。本文系统梳理了IVH后神经炎症的核心作用,阐述干细胞移植通过多重机制抑制神经炎症的治疗潜力。
- Abstract:
- Intraventricular hemorrhage (IVH) triggers a vigorous neuroinflammatory cascade of inducing secondary white-matter injury and long-term neurodevelopmental impairment.Current managements remain largely supportive-primarily cerebrospinal fluid diversion for post-hemorrhagic hydrocephalus-and neither interrupts post-hemorrhagic inflammatory cascade nor promotes neural repair.In recent years,stem cells and their extracellular vesicles (EVs) have emerged as promising disease-modifying candidates owing to their multipotency,low immunogenicity,potent paracrine signaling and capacity for immune reprogramming.This review focused upon the central role of neuroinflammation after IVH and surmised that stem cell transplantation may suppress neuroinflammation through complementary mechanisms.Nevertheless,consensus is lacking regarding optimal cell sources,dosage,routes or timing.And concerns about tumorigenicity and durability of neurodevelopmental benefits require confirmation through adequately powered randomized controlled trials.Future directions include integrating multi-omic platforms for defining responsive endotypes,designing individualized transplantation regimens and validating rational combination strategies for accelerating clinical translation from bench to bedside.Collectively,these efforts aimed to design an evidence-based,safe and effective etiology-targeted therapy for IVH.
参考文献/References:
[1] Komiotis C,Mavridis I.The role of stem cells in the management of neonatal posthemorrhagic hydrocephalus[J].Childs Nerv Syst,2024,41(1):40.DOI:10.1007/s00381-024-06703-2.
[2] 洪菲,张敏,韩树萍,等.胎龄<32周早产儿脑室周围--脑室内出血进展的危险因素分析[J].临床小儿外科杂志,2025,24(8):745-751.DOI:10.3760/cma.j.cn101785-202406010-008. Hong F,Zhang M,Han SP,et al.Analysis of risk factors for progression of periventricular-intraventricular hemorrhage in preterm infants with gestational age <32 weeks[J].J Clin Ped Sur,2025,24(8):745-751.DOI:10.3760/cma.j.cn101785-202406010-008.
[3] 刘祎,秦齐,张佳,等.婴幼儿脑室出血后脑积水的危险因素分析[J].临床小儿外科杂志,2024,23(3):242-246.DOI:10.3760/cma.j.cn101785-202208008-008. Liu Y,Qin Q,Zhang J,et al.Analysis of risk factors of hydrocephalus after intraventricular hemorrhage in infants[J].J Clin Ped Sur,2024,23(3):242-246.DOI:10.3760/cma.j.cn101785-202208008-008.
[4] Scott TE,Aboudi D,Kase JS.Low-grade intraventricular hemorrhage and neurodevelopmental outcomes at 24-42 months of age[J].J Child Neurol,2020,35(9):578-584.DOI:10.1177/0883073820922638.
[5] Dermitzaki N,Baltogianni M,Tsiogka CM,et al.Promising preventive strategies for intraventricular hemorrhage in preterm neonates: a critical review[J].J Clin Med,2025,14(19):6763.DOI:10.3390/jcm14196763.
[6] Fernández-Mu?oz B,Rosell-Valle C,Ferrari D,et al.Retrieval of germinal zone neural stem cells from the cerebrospinal fluid of premature infants with intraventricular hemorrhage[J].Stem Cells Transl Med,2020,9(9):1085-1101.DOI:10.1002/sctm.19-0323.
[7] Dunbar EG,Vegiraju T,Carlson AP.Continuous ventricular irrigation for intraventricular hemorrhage[J].Curr Neurol Neurosci Rep,2025,25(1):78.DOI: 10.1007/s11910-025-01468-w.
[8] Langley EA,Blake SM,Coe KL.Recent review of germinal matrix hemorrhage-intraventricular hemorrhage in preterm infants[J].Neonatal Netw,2022,41(2):100-106.DOI:10.1891/11-T-722.
[9] Deger J,Goethe EA,LoPresti MA,et al.Intraventricular hemorrhage in premature infants: a historical review[J].World Neurosurg,2021,153: 21-25.DOI: 10.1016/j.wneu.2021.06.043.
[10] Holste KG,Xia F,Ye FH,et al.Mechanisms of neuroinflammation in hydrocephalus after intraventricular hemorrhage: a review[J].Fluids Barriers CNS,2022,19(1):28.DOI:10.1186/s12987-022-00324-0.
[11] Christensen R,Cizmeci MN,de Vries LS.Preterm hemorrhagic brain injury: recent advances on evaluation and management[J].Clin Perinatol,2025,52(2): 307-319.DOI:10.1016/j.clp.2025.02.007.
[12] Garton T,Hua Y,Xiang JM,et al.Challenges for intraventricular hemorrhage research and emerging therapeutic targets[J].Expert Opin Ther Targets,2017,21(12):1111-1122.DOI:10.1080/14728222.2017.1397628.
[13] Guo J,Chen QW,Tang J,et al.Minocycline-induced attenuation of iron overload and brain injury after experimental germinal matrix hemorrhage[J].Brain Res,2015,1594:115-124.DOI:10.1016/j.brainres.2014.10.046.
[14] Bulters D,Gaastra B,Zolnourian A,et al.Haemoglobin scavenging in intracranial bleeding: biology and clinical implications[J].Nat Rev Neurol,2018,14(7):416-432.DOI:10.1038/s41582-018-0020-0.
[15] Klebe D,McBride D,Flores JJ,et al.Modulating the immune response towards a neuroregenerative peri-injury milieu after cerebral hemorrhage[J].J Neuroimmune Pharmacol,2015,10(4):576-586.DOI:10.1007/s11481-015-9613-1.
[16] Zhan CH,Xiao GL,Zhang XY,et al.Decreased MiR-30a promotes TGF-β1-mediated arachnoid fibrosis in post-hemorrhagic hydrocephalus[J].Transl Neurosci,2020,11(1):60-74.DOI:10.1515/tnsci-2020-0010.
[17] Fejes Z,Pócsi M,Takai J,et al.Preterm intraventricular hemorrhage-induced inflammatory response in human choroid plexus epithelial cells[J].Int J Mol Sci,2021,22(16):8648.DOI:10.3390/ijms22168648.
[18] Zamorano M,Olson SD,Haase C,et al.Innate immune activation and white matter injury in a rat model of neonatal intraventricular hemorrhage are dependent on developmental stage[J].Exp Neurol,2023,367:114472.DOI:10.1016/j.expneurol.2023.114472.
[19] Jeong SW,Chu K,Jung KH,et al.Human neural stem cell transplantation promotes functional recovery in rats with experimental intracerebral hemorrhage[J].Stroke,2003,34(9):2258-2263.DOI:10.1161/01.STR.0000083698.20199.1F.
[20] Ahn SY,Chang YS,Sung DK,et al.Mesenchymal stem cells prevent hydrocephalus after severe intraventricular hemorrhage[J].Stroke,2013,44(2): 497-504.DOI:10.1161/STROKEAHA.112.679092.
[21] Ahn SY,Chang YS,Sung SI,et al.Mesenchymal stem cells for severe intraventricular hemorrhage in preterm infants: phase I dose-escalation clinical trial[J].Stem Cells Transl Med,2018,7(12):847-856.DOI:10.1002/sctm.17-0219.
[22] Keller T,K?rber F,Oberthuer A,et al.Intranasal breast milk for premature infants with severe intraventricular hemorrhage-an observation[J].Eur J Pediatr,2019,178(2):199-206.DOI:10.1007/s00431-018-3279-7.
[23] Ahn SY,Sung DK,Kim YE,et al.Brain-derived neurotropic factor mediates neuroprotection of mesenchymal stem cell-derived extracellular vesicles against severe intraventricular hemorrhage in newborn rats[J].Stem Cells Transl Med,2021,10(3):374-384.DOI:10.1002/sctm.20-0301.
[24] Ahn SY,Chang YS,Sung DK,et al.Pivotal role of brain-derived neurotrophic factor secreted by mesenchymal stem cells in severe intraventricular hemorrhage in newborn rats[J].Cell Transplant,2017,26(1):145-156.DOI:10.3727/096368916X692861.
[25] Grade S,Weng YC,Snapyan M,et al.Brain-derived neurotrophic factor promotes vasculature-associated migration of neuronal precursors toward the ischemic striatum[J].PLoS One,2013,8(1):e55039.DOI:10.1371/journal.pone.0055039.
[26] Park WS,Ahn SY,Sung SI,et al.Mesenchymal stem cells: the magic cure for intraventricular hemorrhage?[J].Cell Transplant,2017,26(3):439-448.DOI:10.3727/096368916X694193.
[27] Romantsik O,Moreira A,Thébaud B,et al.Stem cell-based interventions for the prevention and treatment of intraventricular haemorrhage and encephalopathy of prematurity in preterm infants[J].Cochrane Database Syst Rev,2023,2(2): CD013201.DOI:10.1002/14651858.CD013201.pub3.
[28] Kim S,Kim YE,Hong S,et al.Reactive microglia and astrocytes in neonatal intraventricular hemorrhage model are blocked by mesenchymal stem cells[J].Glia,2020,68(1):178-192.DOI:10.1002/glia.23712.
[29] Tang J,Jila SJ,Luo TT,et al.C3/C3aR inhibition alleviates GMH-IVH-induced hydrocephalus by preventing microglia-astrocyte interactions in neonatal rats[J].Neuropharmacology,2022,205:108927.DOI:10.1016/j.neuropharm.2021.108927.
[30] Alshareef M,Hatchell D,Vasas T,et al.Complement drives chronic inflammation and progressive hydrocephalus in murine neonatal germinal matrix hemorrhage[J].Int J Mol Sci,2023,24(12): 10171.DOI: 10.3390/ijms241210171.
[31] Donega V,van Velthoven CTJ,Nijboer CH,et al.Intranasal mesenchymal stem cell treatment for neonatal brain damage: long-term cognitive and sensorimotor improvement[J].PLoS One,2013,8(1):e51253.DOI:10.1371/journal.pone.0051253.
[32] Hoban R,Gallipoli A,Signorile M,et al.Feasibility of intranasal human milk as stem cell therapy in preterm infants with intraventricular hemorrhage[J].J Perinatol,2024,44(11):1652-1657.DOI:10.1038/s41372-024-01982-8.
[33] Habiyaremye G,Morales DM,Morgan CD,et al.Chemokine and cytokine levels in the lumbar cerebrospinal fluid of preterm infants with post-hemorrhagic hydrocephalus[J].Fluids Barriers CNS,2017,14(1):35.DOI:10.1186/s12987-017-0083-0.
[34] van Velthoven CTJ,Kavelaars A,van Bel F,et al.Nasal administration of stem cells: a promising novel route to treat neonatal ischemic brain damage[J].Pediatr Res,2010,68(5):419-422.DOI:10.1203/PDR.0b013e3181f1c289.
[35] Razak A,Connelly K,Hunt RW,et al.Safety and feasibility of allogeneic cord blood-derived cell therapy in preterm infants with severe brain injury (ALLO trial): a phase-1 trial protocol[J].BMJ Open,2025,15(6):e100389.DOI:10.1136/bmjopen-2025-100389.
[36] Gao L,Li PP,Shao TY,et al.Neurotoxic role of interleukin-17 in neural stem cell differentiation after intracerebral hemorrhage[J].Neural Regen Res,2020,15(7):1350-1359.DOI:10.4103/1673-5374.272614.
[37] Yang GQ,Kantapan J,Mazhar M,et al.Mesenchymal stem cells transplantation combined with IronQ attenuates ICH-induced inflammation response via Mincle/syk signaling pathway[J].Stem Cell Res Ther,2023,14(1):131.DOI:10.1186/s13287-023-03369-6.
[38] Seah C,Schuldt BR,Vicari JM,et al.Single-cell sequencing of human neural organoids in a model of intracerebral hemorrhage reveals temporally dynamic responses to blood[J].Stroke,2025,56(11):3294-3305.DOI:10.1161/STROKEAHA.125.051788.
[39] Kim MS,Kim DH,Kang HK,et al.Modeling of hypoxic brain injury through 3D human neural organoids[J].Cells,2021,10(2):234.DOI:10.3390/cells10020234.
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备注/Memo
收稿日期:2025-10-29。
基金项目:广东省自然科学基金(2024A1515012949);广州市科技局重点研发计划(2024B03J0352)
通讯作者:宋烨,Email:songye0724@126.com