Dedifferentiated human umbilical cord mesenchymal stem cell reprogramming of endogenous hSDF-1α expression participates in neural restoration in hypoxic-ischemic brain damage rats

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Abstract

The transplantation of human umbilical cord mesenchymal stem cells (hUC-MSCs) can promote hypoxic-ischemic brain damage (HIBD) nerve repair, but finding suitable seed cells to optimize transplantation and improve treatment efficiency is an urgent problem to be solved. In this study, we induced hUC-MSCs into dedifferentiated hUC-MSCs (De-hUC-MSCs), and the morphology, stem cell surface markers, proliferation and tri-directional differentiation ability of the De-hUC-MSCs and hUC-MSCs were detected. A whole-gene chip was utilized for genome cluster, gene ontology and KEGG pathway analyses of differentially expressed genes. De-hUC-MSCs were transplanted into HIBD rats, and behavioral experiments and immunofluorescence assays were used to assess the therapeutic effect. A lentivirus vector for human stromal cell-derived factor-1 (hSDF-1α) was constructed, and the role of hSDF-1α in the neuroprotective effect and mechanism of De-hUC-MSCs was verified. De-hUC-MSCs displayed similar cell morphology, stem cell surface marker expression, cell proliferation and even three-dimensional differentiation ability as hUC-MSCs but exhibited greater treatment potential in vivo. The reprogramming mechanism of hSDF-1α participated in the dedifferentiation process. By successfully constructing a stable hSDF-1α cell line, we found that De-hUC-MSCs might participate in nerve repair through the hSDF-1α/CXCR4/PI3K/Akt pathway. De-hUC-MSCs reprogramming of endogenous hSDF-1α expression may mediate the hSDF-1α/CXCR4/PI3K/Akt pathway involved in nerve repair in HIBD rats.

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The influence of immaturity on hypoxic-ischemic brain damage in the rat.

J E Rice, R C Vannucci, J B Brierley (1981)

Brain damage in the Levine preparation (unilateral common carotid artery ligation with hypoxia) consists of ischemic neuronal alterations in the ipsilateral forebrain. As the model has been restricted to adult animals, unilateral common carotid artery ligation was carried out in 7-day-postnatal rats. Four to 8 hours later the 25 pups were exposed to 8% oxygen at 37 degrees C for 3.5 hours. Controls consisted of littermates subjected to carotid ligation without subsequent hypoxia, hypoxia without prior ligation, and neither ligation nor hypoxia. After hypoxia the animals were returned to their dams and appeared normal for up to 50 hours. All pups were then killed by perfusion-fixation. Moderate to severe ischemic neuronal changes were seen in the ipsilateral cerebral cortex, striatum, and hippocampus in at least 90% of the animals and included infarction in 56% of the brains. Cortical damage was occasionally laminar but more often occurred in columns at right angles to the pial surface. Unlike adult animals, there was necrosis of white matter, greater ipsilaterally, originating in and spreading from myelinogenic foci. The evolution of ischemic cell change and the associated gliomesodermal reaction was more rapid than in the adult. In 22 additional pups subjected to carotid artery ligation and hypoxia, brains were analyzed for water content. Significant increases (0.6 to 3.3%) in water content of the ipsilateral hemispheres occurred in 11 of 22 brains (50%). Unilateral ischemia combined with hypoxia in developing rats therefore results in neuronal destruction in the same brain regions as in adult animals, but also causes necrosis of white matter. The incidence of increased water content was similar to that of overt infarction. Thus, as previously shown in the adult, brain edema is a consequence rather than a cause of major ischemic damage in the immature animal.

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Cell based therapies for ischemic stroke: from basic science to bedside.

Mao-ling Wei, Xinying Fan, S. S. Yu … (2014)

Cell therapy is emerging as a viable therapy to restore neurological function after stroke. Many types of stem/progenitor cells from different sources have been explored for their feasibility and efficacy for the treatment of stroke. Transplanted cells not only have the potential to replace the lost circuitry, but also produce growth and trophic factors, or stimulate the release of such factors from host brain cells, thereby enhancing endogenous brain repair processes. Although stem/progenitor cells have shown a promising role in ischemic stroke in experimental studies as well as initial clinical pilot studies, cellular therapy is still at an early stage in humans. Many critical issues need to be addressed including the therapeutic time window, cell type selection, delivery route, and in vivo monitoring of their migration pattern. This review attempts to provide a comprehensive synopsis of preclinical evidence and clinical experience of various donor cell types, their restorative mechanisms, delivery routes, imaging strategies, future prospects and challenges for translating cell therapies as a neurorestorative regimen in clinical applications. Copyright © 2013 Elsevier Ltd. All rights reserved.

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GDF-15 secreted from human umbilical cord blood mesenchymal stem cells delivered through the cerebrospinal fluid promotes hippocampal neurogenesis and synaptic activity in an Alzheimer's disease model.

Dong Hyun Kim, Dahm Lee, Eun Hyuk Chang … (2015)

Our previous studies demonstrated that transplantation of human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) into the hippocampus of a transgenic mouse model of Alzheimer's disease (AD) reduced amyloid-β (Aβ) plaques and enhanced cognitive function through paracrine action. Due to the limited life span of hUCB-MSCs after their transplantation, the extension of hUCB-MSC efficacy was essential for AD treatment. In this study, we show that repeated cisterna magna injections of hUCB-MSCs activated endogenous hippocampal neurogenesis and significantly reduced Aβ42 levels. To identify the paracrine factors released from the hUCB-MSCs that stimulated endogenous hippocampal neurogenesis in the dentate gyrus, we cocultured adult mouse neural stem cells (NSCs) with hUCB-MSCs and analyzed the cocultured media with cytokine arrays. Growth differentiation factor-15 (GDF-15) levels were significantly increased in the media. GDF-15 suppression in hUCB-MSCs with GDF-15 small interfering RNA reduced the proliferation of NSCs in cocultures. Conversely, recombinant GDF-15 treatment in both in vitro and in vivo enhanced hippocampal NSC proliferation and neuronal differentiation. Repeated administration of hUBC-MSCs markedly promoted the expression of synaptic vesicle markers, including synaptophysin, which are downregulated in patients with AD. In addition, in vitro synaptic activity through GDF-15 was promoted. Taken together, these results indicated that repeated cisterna magna administration of hUCB-MSCs enhanced endogenous adult hippocampal neurogenesis and synaptic activity through a paracrine factor of GDF-15, suggesting a possible role of hUCB-MSCs in future treatment strategies for AD.

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Author and article information

Contributors

Li Tingyu

Zhan Xue

Journal

Journal ID (nlm-ta): Genes Dis

Journal ID (iso-abbrev): Genes Dis

Title: Genes & Diseases

Publisher: Chongqing Medical University

ISSN (Print): 2352-4820

ISSN (Electronic): 2352-3042

Publication date PMC-release: 18 February 2020

Publication date Collection: May 2021

Publication date (Electronic): 18 February 2020

Volume: 8

Issue: 3

Pages: 331-343

Affiliations

[a ]Department of Gastroenterology, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders (Chongqing), 401122, PR China

[b ]International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, 401122, PR China

[c ]Department of Pediatric Research Institute, Chongqing Key Laboratory of Child Health and Nutrition, Children's Hospital of Chongqing Medical University, Chongqing, 401122, PR China

[d ]Department of Neonatology, Chongqing Health Center for Women and Children, 400021, PR China

[e ]Child Health Centre of Northwest Women and Children's Hospital, USA

Author notes

[∗ ]Corresponding author. zhanxue@ 123456hotmail.com

[∗∗ ]Corresponding author. tyli@ 123456vip.sina.com

[1]

Zhou Xiaoqin and Liu Jia were first co-authors.

Article

Publisher Item ID: S2352-3042(20)30020-9

DOI: 10.1016/j.gendis.2020.01.012

PMC ID: 8093640

SO-VID: d7726b09-27f3-426e-9ca5-0f346b47affc

License:

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Dedifferentiated human umbilical cord mesenchymal stem cell reprogramming of endogenous hSDF-1α expression participates in neural restoration in hypoxic-ischemic brain damage rats

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Genes & Diseases

Most cited references 30

The influence of immaturity on hypoxic-ischemic brain damage in the rat.

Cell based therapies for ischemic stroke: from basic science to bedside.

GDF-15 secreted from human umbilical cord blood mesenchymal stem cells delivered through the cerebrospinal fluid promotes hippocampal neurogenesis and synaptic activity in an Alzheimer's disease model.

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