Promoting Effect of Wnt-3a and Stem Cell Factor Treatments on Cell Protection, Neurogenesis, Angiogenesis and Functional Recovery in Focal Ischemic Stroke Mice Open Access

Liu, Chenyu (2016)

Permanent URL: https://etd.library.emory.edu/concern/etds/9p290996t?locale=en
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Abstract

Stroke is the third leading cause of death and a major cause of serious and long-term disability in the United States; however, very limited effective treatments are available for stroke patients. This study is aimed at finding a novel regenerative treatment for focal ischemic stroke by using stem cell factor (SCF) and Wnt-3a proteins. The Wnt-3a signaling pathway, through mediating gene expression and the β-catenin protein, is capable of inducing stem cell differentiation and migration, enabling it to be a potent neurogenesis agent. SCF, on the other hand, can promote angiogenesis by directly activating microvascular endothelial cells in the CNS. Because increasing vascularization of the ischemic penumbra region can help deliver more oxygen and nutrients, this should facilitate the process of neurogenesis and exert a synergistic therapeutic effect. Ultimately, we wanted to restore the neuro-vascular unit for functional recovery. We hypothesized that the combined treatment of Wnt-3a and SCF may work synergistically in treating stroke. Treatment was administered intranasally for 7 days, started on the day of stroke surgery. Immunohistochemical staining was used to quantify neurogenesis and angiogenesis. All treatment groups showed enhanced neurogenesis and angiogenesis, but no synergistic effect of the SCF/Wnt-3a combined group was observed. All treatment groups illustrated a cell protective effect as shown by Western blot analysis, and a synergistic effect was observed in the SCF/Wnt-3a combined group. Additionally, the sticky dots behavioral test was used to measure sensorimotor functional recovery. All treatment groups showed improved sensorimotor function, yet only a non-significant trend of synergy was observed. Based on all our results, we concluded that SCF, Wnt-3a and SCF/Wnt-3a combined treatments all demonstrated a therapeutic effect on focal ischemia stroke. Our current data partially support the hypothesis. Considering that regeneration is a long-term process, further investigation at delayed time points will be necessary to test our hypothesis.

Table of Contents

TABLE OF CONTENTS

Terminology and abbreviations…….…….…….…….…….…….…….…….…….…….1

Abstract…….…….…….…….…….…….…….…….…….……….…….…….…….…..2

Introduction….…….…….…….…….…….…….…….……….…….…….……….…….4

· Why study ischemic stroke: Pathophysiology of ischemic stroke

· Focal Ischemia Stroke: the Barrel Cortex

· Current therapy of Ischemic Stroke: Thrombolysis and Neuroprotection

· Intranasal Delivery Of Treatment

· Wnt Signal Transduction Pathway and Neurogenesis Potential

· Stem Cell Factor Signaling Pathway and Angiogenesis Potential

Materials and Methods….…….……….…….…….……….…….…….………………15

· Ischemia Animal Model:

· Experimental Groups and Drug Administrations:

· BrdU Administrations

· Coronal Sectioning and Tissue preparations

· Immunohistochemical Staining

· Cell Counting

· Western Blot Analysis

· Behavior Assessment

· Statistical Analyses

Results…….…….…….…….…….…….…….…….…….……….…….…….…….…..20

Figures…….…….…….…….…….…….…….…….…….……….…….…….…….…..22

· Figure 1. Both SCF and Wnt treatments enhanced neurogenesis.

· Figure 2. SCF and SCF+Wnt combined treatment groups showed enhanced angiogenesis.

· Figure 3. Wnt3a, SCF, and the co-treatment after stroke in mice showed cell protective effect.

· Figure 4. SCF, Wnt and SCF/Wnt combined treatment significantly improved sensorimotor function recovery.

Discussion…….…….…….……….…….…….……….…….…….……….…….……..27

· Histology data of Neurogenesis and Angiogenesis

· Western Blot Analysis Of Cell Protection Effects

· Behavioral Assessment And Functional Recovery

Limitations…….…….…….……….…….…….……….…….…….……….…….…….33

References…….…….…….……….…….…….……….…….…….……….…….……..34

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