Neocortical tissue recovery in severe congenital obstructive hydrocephalus after intraventricular administration of bone marrow-derived mesenchymal stem cells

García-Bonilla, María; Ojeda-Pérez, Betsaida; García-Martín, María Luisa; Muñoz-Hernández, M. Carmen; Vitórica, Javier; Jiménez, Sebastián; Cifuentes, Manuel; Santos-Ruíz, Leonor; Shumilov, Kirill; Claros, Silvia; Gutiérrez, Antonia; Paéz-González, Patricia; Jiménez, Antonio J.

doi:10.1186/s13287-020-01626-6

Cited by 10 publications

(24 citation statements)

References 76 publications

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“…The expression of some stem cell markers was studied to confirm that BM-MSCs did not transdifferentiate after transplantation. Transplanted BM-MSCs maintained the expression of nestin (detected with the antibody Rat-401), NG2, βIII-tubulin, δGFAP, and αGFAP ( Figure 1 d–h) in the same way as they did in vitro (for details, see [ 17 ]) indicating no transdifferentiation. NG2, βIII-tubulin, and αGFAP immunoreactions in the transplanted BM-MSCs were weak compared to the corresponding labeling in oligodendrocyte progenitors, neuroblasts, or astrocytes, respectively.…”

Section: Resultsmentioning

confidence: 74%

“…Various stem cell therapies have been assayed in experimental forms of congenital and acquired feto-neonatal hydrocephalus. Neural stem cells [ 15 ] and mesenchymal stem cells [ 16 , 17 ] have shown promising results in hydrocephalus of obstructive and posthemorrhagic origins. In neurodegenerative diseases, bone marrow-derived mesenchymal stem cells (BM-MSCs) were shown to play a neuroprotective role due to their capacity to migrate to degenerated regions and produce different growth factors [ 18 , 19 ].…”

Section: Introductionmentioning

confidence: 99%

“…In a previous study in hyh mice, BM-MSCs were injected into the lateral ventricle, and they were attracted and hosted by reactive astrocytes of the white matter [ 17 ]. The periventricular astrocyte reaction is a key event in hydrocephalus development [ 6 , 25 , 27 , 28 , 29 ].…”

Section: Introductionmentioning

confidence: 99%

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Generation of Periventricular Reactive Astrocytes Overexpressing Aquaporin 4 Is Stimulated by Mesenchymal Stem Cell Therapy

García-Bonilla

Ojeda-Pérez

Shumilov

et al. 2023

IJMS

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Aquaporin-4 (AQP4) plays a crucial role in brain water circulation and is considered a therapeutic target in hydrocephalus. Congenital hydrocephalus is associated with a reaction of astrocytes in the periventricular white matter both in experimental models and human cases. A previous report showed that bone marrow-derived mesenchymal stem cells (BM-MSCs) transplanted into the lateral ventricles of hyh mice exhibiting severe congenital hydrocephalus are attracted by the periventricular astrocyte reaction, and the cerebral tissue displays recovery. The present investigation aimed to test the effect of BM-MSC treatment on astrocyte reaction formation. BM-MSCs were injected into the lateral ventricles of four-day-old hyh mice, and the periventricular reaction was detected two weeks later. A protein expression analysis of the cerebral tissue differentiated the BM-MSC-treated mice from the controls and revealed effects on neural development. In in vivo and in vitro experiments, BM-MSCs stimulated the generation of periventricular reactive astrocytes overexpressing AQP4 and its regulatory protein kinase D-interacting substrate of 220 kDa (Kidins220). In the cerebral tissue, mRNA overexpression of nerve growth factor (NGF), vascular endothelial growth factor (VEGF), hypoxia-inducible factor-1 (HIF1α), and transforming growth factor beta 1 (TGFβ1) could be related to the regulation of the astrocyte reaction and AQP4 expression. In conclusion, BM-MSC treatment in hydrocephalus can stimulate a key developmental process such as the periventricular astrocyte reaction, where AQP4 overexpression could be implicated in tissue recovery.

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Section: Resultsmentioning

confidence: 74%

Section: Introductionmentioning

confidence: 99%

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Generation of Periventricular Reactive Astrocytes Overexpressing Aquaporin 4 Is Stimulated by Mesenchymal Stem Cell Therapy

García-Bonilla

Ojeda-Pérez

Shumilov

et al. 2023

IJMS

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“…In rodent studies in 2013 and 2015, it was found that implantation of mesenchymal stem cells (MSCs) in the ventricular wall resulted in the prevention of the progression of hydrocephalus as well as the neurorepair of the injured site [ 69 , 108 ]. An additional study in 2020 confirmed that MSC implantation in the ventricular wall resulted in a decrease in inflammation, and an increase in neurorepair which rescued the neurodegeneration due to hydrocephalus [ 109 ]. Additionally, in 2018 a Phase I clinical trial was completed which evaluated the safety and tolerability of MSC grafts in pediatric hydrocephalus patients.…”

Section: Resultsmentioning

confidence: 99%

Hydrocephalus: historical analysis and considerations for treatment

2022

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Hydrocephalus is a serious condition that affects patients of all ages, resulting from a multitude of causes. While the etiologies of hydrocephalus are numerous, many of the acute and chronic symptoms of the condition are shared. These symptoms include disorientation and pain (headaches), cognitive and developmental changes, vision and sleep disturbances, and gait abnormalities. This collective group of symptoms combined with the effectiveness of CSF diversion as a surgical intervention for many types of the condition suggest that the various etiologies may share common cellular and molecular dysfunctions. The incidence rate of pediatric hydrocephalus is approximately 0.1–0.6% of live births, making it as common as Down syndrome in infants. Diagnosis and treatment of various forms of adult hydrocephalus remain understudied and underreported. Surgical interventions to treat hydrocephalus, though lifesaving, have a high incidence of failure. Previously tested pharmacotherapies for the treatment of hydrocephalus have resulted in net zero or negative outcomes for patients potentially due to the lack of understanding of the cellular and molecular mechanisms that contribute to the development of hydrocephalus. Very few well-validated drug targets have been proposed for therapy; most of these have been within the last 5 years. Within the last 50 years, there have been only incremental improvements in surgical treatments for hydrocephalus, and there has been little progress made towards prevention or cure. This demonstrates the need to develop nonsurgical interventions for the treatment of hydrocephalus regardless of etiology. The development of new treatment paradigms relies heavily on investment in researching the common molecular mechanisms that contribute to all of the forms of hydrocephalus, and requires the concerted support of patient advocacy organizations, government- and private-funded research, biotechnology and pharmaceutical companies, the medical device industry, and the vast network of healthcare professionals.

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“…Also, it is not probable that such notable changes in phosphatidylserine levels detected in the present study were implied in apoptosis. We have previously shown that the apoptosis rate in the neocortical grey matter of the hyh mice is low, non-detectable [ 61 ]. Thus, apoptosis only can be detected in the periventricular white matter of hyh mice.…”

Section: Discussionmentioning

confidence: 99%

Identification of key molecular biomarkers involved in reactive and neurodegenerative processes present in inherited congenital hydrocephalus

Ojeda-Pérez

Campos-Sandoval

García-Bonilla

et al. 2021

Fluids Barriers CNS

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Background Periventricular extracellular oedema, myelin damage, inflammation, and glial reactions are common neuropathological events that occur in the brain in congenital hydrocephalus. The periventricular white matter is the most affected region. The present study aimed to identify altered molecular and cellular biomarkers in the neocortex that can function as potential therapeutic targets to both treat and evaluate recovery from these neurodegenerative conditions. The hyh mouse model of hereditary hydrocephalus was used for this purpose. Methods The hyh mouse model of hereditary hydrocephalus (hydrocephalus with hop gait) and control littermates without hydrocephalus were used in the present work. In tissue sections, the ionic content was investigated using energy dispersive X-ray spectroscopy scanning electron microscopy (EDS-SEM). For the lipid analysis, matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI) was performed in frozen sections. The expression of proteins in the cerebral white matter was analysed by mass spectrometry. The oligodendrocyte progenitor cells (OPCs) were studied with immunofluorescence in cerebral sections and whole-mount preparations of the ventricle walls. Results High sodium and chloride concentrations were found indicating oedema conditions in both the periventricular white matter and extending towards the grey matter. Lipid analysis revealed lower levels of two phosphatidylinositol molecular species in the grey matter, indicating that neural functions were altered in the hydrocephalic mice. In addition, the expression of proteins in the cerebral white matter revealed evident deregulation of the processes of oligodendrocyte differentiation and myelination. Because of the changes in oligodendrocyte differentiation in the white matter, OPCs were also studied. In hydrocephalic mice, OPCs were found to be reactive, overexpressing the NG2 antigen but not giving rise to an increase in mature oligodendrocytes. The higher levels of the NG2 antigen, diacylglycerophosphoserine and possibly transthyretin in the cerebrum of hydrocephalic hyh mice could indicate cell reactions that may have been triggered by inflammation, neurocytotoxic conditions, and ischaemia. Conclusion Our results identify possible biomarkers of hydrocephalus in the cerebral grey and white matter. In the white matter, OPCs could be reacting to acquire a neuroprotective role or as a delay in the oligodendrocyte maturation.

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Neocortical tissue recovery in severe congenital obstructive hydrocephalus after intraventricular administration of bone marrow-derived mesenchymal stem cells

Cited by 10 publications

References 76 publications

Generation of Periventricular Reactive Astrocytes Overexpressing Aquaporin 4 Is Stimulated by Mesenchymal Stem Cell Therapy

Generation of Periventricular Reactive Astrocytes Overexpressing Aquaporin 4 Is Stimulated by Mesenchymal Stem Cell Therapy

Hydrocephalus: historical analysis and considerations for treatment

Identification of key molecular biomarkers involved in reactive and neurodegenerative processes present in inherited congenital hydrocephalus

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