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1.
Adv Exp Med Biol. 2016;923:37-42. doi: 10.1007/978-3-319-38810-6_5.

Hypoxia-Induced Let-7d Has a Role in Pericyte Differentiation.

Author information

1
Department of Neurology, Medical School, Wayne State University, Elliman Building, Rm 3125, 421 E. Canfield Str., Detroit, MI, 48201, USA. nesenbil@med.wayne.edu.
2
Department of Neurology, Wayne State University, Detroit, MI, USA.
3
Department of Neurological Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA.

Abstract

The microvascular pericyte is an important regulatory cell that maintains tissue homeostasis. One of the mechanisms by which pericytes maintain tissue homeostasis is through the induction of endogenous adaptative changes to stress signals. These adaptations include migration, differentiation and induction of angiogenesis. We have investigated pericyte responses to hypoxic stress (1‚ÄČ% O2) and have reported that pericytes adapt to hypoxia, in part, through changes in endogenous and released microRNAs (miRNAs). Of those miRNAs, Let-7d plays an important role. We exposed pericytes to hypoxia with and without basic fibroblast growth factor (bFGF) in stem cell medium. The expression of Let-7d in pericyte-derived neurospheres was determined. Evidence of differentiation was determined by immunocytochemistry. Hypoxia enhanced pericyte spheres were positive for Let-7d. The transcription factor Sox2, a marker of cell differentiation, was also induced in pericytic spheres. Taken together, our results suggest that pericyte expression of Let-7d in response to hypoxia and bFGF is involved in pericyte differentiation. Thus, for the first time, we propose a pathway for induction of pericyte differentiation. Modulation of this pathway in pericytes may be an important target in tissue repair.

KEYWORDS:

Differentiation; Hypoxia; Let-7d; Pericytes; microRNA

PMID:
27526122
DOI:
10.1007/978-3-319-38810-6_5
[Indexed for MEDLINE]
Icon for Springer
2.
J Neuroinflammation. 2016 Jan 19;13:13. doi: 10.1186/s12974-015-0407-4.

Endogenous adaptation to low oxygen modulates T-cell regulatory pathways in EAE.

Author information

1
Department of Neurology, School of Medicine, Wayne State University, Detroit, MI, 48201, USA. nesenbil@med.wayne.edu.
2
Department of Neurology, School of Medicine, Wayne State University, Detroit, MI, 48201, USA. vkatyshev@med.wayne.edu.
3
Department of Neurology, School of Medicine, Wayne State University, Detroit, MI, 48201, USA. zserki@med.wayne.edu.
4
Department of Neurology, School of Medicine, Wayne State University, Detroit, MI, 48201, USA. skatyshe@med.wayne.edu.
5
Department of Neurology, School of Medicine, Wayne State University, Detroit, MI, 48201, USA. pdduffy@med.wayne.edu.

Abstract

BACKGROUND:

In the brain, chronic inflammatory activity may lead to compromised delivery of oxygen and glucose suggesting that therapeutic approaches aimed at restoring metabolic balance may be useful. In vivo exposure to chronic mild normobaric hypoxia (10 % oxygen) leads to a number of endogenous adaptations that includes vascular remodeling (angioplasticity). Angioplasticity promotes tissue survival. We have previously shown that induction of adaptive angioplasticity modulates the disease pattern in myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE). In the present study, we define mechanisms by which adaptation to low oxygen functionally ameliorates the signs and symptoms of EAE and for the first time show that tissue hypoxia may fundamentally alter neurodegenerative disease.

METHODS:

C57BL/6 mice were immunized with MOG, and some of them were kept in the hypoxia chambers (day 0) and exposed to 10 % oxygen for 3 weeks, while the others were kept at normoxic environment. Sham-immunized controls were included in both hypoxic and normoxic groups. Animals were sacrificed at pre-clinical and peak disease periods for tissue collection and analysis.

RESULTS:

Exposure to mild hypoxia decreased histological evidence of inflammation. Decreased numbers of cluster of differentiation (CD)4+ T cells were found in the hypoxic spinal cords associated with a delayed Th17-specific cytokine response. Hypoxia-induced changes did not alter the sensitization of peripheral T cells to the MOG peptide. Exposure to mild hypoxia induced significant increases in anti-inflammatory IL-10 levels and an increase in the number of spinal cord CD25+FoxP3+ T-regulatory cells.

CONCLUSIONS:

Acclimatization to mild hypoxia incites a number of endogenous adaptations that induces an anti-inflammatory milieu. Further understanding of these mechanisms system may pinpoint possible new therapeutic targets to treat neurodegenerative disease.

PMID:
26785841
PMCID:
PMC4717549
DOI:
10.1186/s12974-015-0407-4
[Indexed for MEDLINE]
Free PMC Article
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3.
Methods Mol Biol. 2014;1135:35-52. doi: 10.1007/978-1-4939-0320-7_4.

Pericytes and adaptive angioplasticity: the role of tumor necrosis factor-like weak inducer of apoptosis (TWEAK).

Author information

1
Division of Neuroimmunology, Department of Neurology, Wayne State University School of Medicine, Detroit, MI, USA.

Abstract

The TNF superfamily member TWEAK has emerged as a pleiotropic cytokine that regulates many cellular functions that include immune/inflammatory activity, angiogenesis, cell proliferation, and fate. TWEAK through its inducible receptor, FGF-inducible molecule 14 (Fn14), can induce both beneficial and deleterious activity that has a profound effect on cell survival. Thus it is highly likely that TWEAK and Fn14 expressed by cells of the neurovascular unit help regulate and maintain vascular and tissue homeostasis. In this chapter we discuss the expression of TWEAK and Fn14 signaling in the cerebral microvascular pericyte. Pericytes are a highly enigmatic population of microvascular cells that are important in regulatory pathways that modulate physiological angiogenesis in response to chronic mild hypoxic stress. A brief introduction will identify the microvascular pericyte. A more detailed discussion of pericyte TWEAK signaling during adaptive angioplasticity will follow.

PMID:
24510853
DOI:
10.1007/978-1-4939-0320-7_4
[Indexed for MEDLINE]
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4.
J Neurol Sci. 2013 Oct 15;333(1-2):88-92. doi: 10.1016/j.jns.2013.06.004. Epub 2013 Jun 28.

Induction of vascular remodeling: a novel therapeutic approach in EAE.

Author information

1
Department of Neurology, Wayne State University School of Medicine, Detroit, MI 48201, United States.

Abstract

While the pathologic events associated with multiple sclerosis (MS), diffuse axonal injury, cognitive damage, and white matter plaques, have been known for some time, their etiology is unknown and therapeutic efforts are still somewhat disappointing. This may be due to a lack of fundamental knowledge on how to maintain tissue homeostasis and buffer the brain from secondary injury. Maintenance of homeostasis in the brain is the result of regulatory adjustments by cellular constituents of the neurovascular unit (pericytes, endothelial cells, astrocytes, and neurons) that include induction of adaptive vascular remodeling. Results from our laboratory and others suggest that aspects of stress induced adaptation are seen in MS and in the murine model of experimental autoimmune encephalomyelitis (EAE), vascular remodeling is ineffective and biometabolic balance is disrupted. In murine white matter, capillary density is 1/2 that observed in gray matter thus disruption of vascular homeostasis will have a profound impact on tissue integrity. We therefore hypothesized that restoration of microvascular angiodynamics would augment tissue plasticity mitigating the extent of secondary injury and sparing cognitive decline in patients with MS. To test this hypothesis, we have performed preclinical studies and characterized changes in angiodynamics in myelin oligodendrocyte glycoprotein (MOG) peptide (35-55)-induced EAE in C57BL/6 mice with or without concomitant exposure to chronic mild low oxygen. We have reported that exposure to chronic mild low oxygen ameliorated clinical disease in EAE. While the mechanisms of protection are unclear, results suggest that normobaric hypoxia stabilizes the stress response, promotes physiological angiogenesis, and is neuroprotective.

KEYWORDS:

Adaptation; Angiogenesis; Chemokines; EAE; Hypoxia; Multiple sclerosis; Pericyte; T cells

PMID:
23810780
DOI:
10.1016/j.jns.2013.06.004
[Indexed for MEDLINE]
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