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MCP-1 AND APP INVOLVEMENT IN GLIAL DIFFERENTIATION AND MIGRATION OF NEUROPROGENITOR CELLS.
Title
MCP-1 AND APP INVOLVEMENT IN GLIAL DIFFERENTIATION AND MIGRATION OF NEUROPROGENITOR CELLS.
Creator
Vrotsos, Emmanuel, Sugaya, Kiminobu, University of Central Florida
Abstract / Description
Neuroprogenitor cells are an important resource because of their potential to replace damaged cells in the brain caused by trauma and disease. It is of great importance to better understand which factors influence the differentiation and migration of these cells. Previously it has been reported that neuroprogenitor cells undergoing apoptotic stress have increased levels of Amyloid precursor protein (APP) and increased APP expression results in glial differentiation. APP activity was also...
Show moreNeuroprogenitor cells are an important resource because of their potential to replace damaged cells in the brain caused by trauma and disease. It is of great importance to better understand which factors influence the differentiation and migration of these cells. Previously it has been reported that neuroprogenitor cells undergoing apoptotic stress have increased levels of Amyloid precursor protein (APP) and increased APP expression results in glial differentiation. APP activity was also shown to be required for staurosporine induced glial differentiation of neuroprogenitor cells. Monocyte chemoattractant protein-1 (MCP-1) is a chemokine that is expressed during inflammatory. The binding of MCP-1 to its chemokine receptor induces expression of novel transcription factor MCP-1 induced protein (MCPIP). MCPIP expression subsequently leads to cell death. Previous studies have shown that pro apoptotic factors have the ability to induce neural differentiation. Therefore, we investigated if MCPIP expression leads to differentiation of NT2 neuroprogenitor cells. Results showed that MCPIP expression increased glial fibrillary acid protein expression and also caused distinct morphological changes, both indicative of glial differentiation. Similar results were observed with MCP-1 treatment. Interestingly, APP expression decreased in response to MCPIP. Instead, we found APP activity regulates expression of both MCP-1 and MCPIP. Furthermore, inhibition of either p38 MAPK or JAK signaling pathways significantly reduced APP's effect on MCP-1 and MCPIP. These data demonstrate the role APP has in glial differentiation of NT2 cells through MCP-1/MCPIP signaling. It is possible that increased APP expression after CNS injury could play a ii role in MCP-1 production, possibly promoting astrocyte activation at injured site. We next investigated the effect that MCP-1 has on NT2 cell migration. Studies have shown that when neuroprogenitor cells are transplanted into the brain they migrate towards damaged areas, suggesting that these areas express factors that recruit migrating cells. Generally, after neuronal injury there is a neuroinflammatory response that results in increased chemokine production. We demonstrate that MCP-1 significantly induces the migration of NT2 neuroprogenitor cells. Activation of intracellular cyclic adenosine monophosphate (cAMP) or protein kinase C with forskolin and phorbol 12-myristate 13-acetate (PMA), respectively, was able to completely abolish the MCP-1 induced migration. Contrarily, neither extracellular signal-regulated kinase or p38 mitogen activated protein kinase was required for NT2 cells to respond to MCP-1. Interestingly, APP's ability to activate MCP-1 expression was shown to play a role in NT2 cell migration. We showed that NT2 cells expressing APP were capable of inducing migration of other neuroprogenitor cells. Utilizing a MCP-1 neutralizing antibody we discovered that APP induced migration was not caused solely by increased MCP-1 production. Interestingly, APP increased expression of several C-C chemokines: MCP-1, Regulated upon Activation, Normal T-cell Expressed, and Secreted (RANTES), and macrophage inflammatory protein alpha (MIP-1 alpha). This demonstrates the unique role APP has in regulating chemokine production, which directly affects cell migration. Taken together, this study provides us with a greater understanding of the mechanisms involved in both glial differentiation and migration of NT2 neuroprogenitor cells.
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Date Issued
2009
Identifier
CFE0002517, ucf:47661
Format
Document (PDF)
PURL
http://purl.flvc.org/ucf/fd/CFE0002517
Probing the Effects of Substrate Stiffness on Astrocytes Mechanics
Title
Probing the Effects of Substrate Stiffness on Astrocytes Mechanics.
Creator
Bizanti, Ariege, Steward, Robert, Samsam, Mohtashem, Huang, Helen, University of Central Florida
Abstract / Description
Astrocytes are among the most functionally diverse population of cells in the central nervous system (CNS) as they are essential to many important neurological functions including maintaining brain homeostasis, regulating the blood brain barrier, and preventing build-up of toxic substances within the brain, for example. Astrocyte importance to brain physiology and pathology has inspired a host of studies focused on understanding astrocyte behavior primarily from a biological and chemical...
Show moreAstrocytes are among the most functionally diverse population of cells in the central nervous system (CNS) as they are essential to many important neurological functions including maintaining brain homeostasis, regulating the blood brain barrier, and preventing build-up of toxic substances within the brain, for example. Astrocyte importance to brain physiology and pathology has inspired a host of studies focused on understanding astrocyte behavior primarily from a biological and chemical perspective. However, a clear understanding of astrocyte dysfunction and their link to disease has been hampered by a lack of knowledge of astrocyte behavior from a biomechanical perspective. Furthermore, astrocytes (and all cells) can sense and respond to their external biomechanical environment via the extracellular matrix and various other biomechanical cues.One such biomechanical cue, substrate stiffness changes within the brain under certain pathologies, which subsequently leads to changes in the biomechanical behavior of the cell. For example, increased tissue stiffness is a hallmark of brain tumors that subsequently alters astrocyte biomechanical behavior. Therefore, to gain a better understanding of this process we cultured astrocytes on stiffnesses that mimicked that of the normal brain, meningioma, and glioma and investigated astrocyte biomechanical behavior by measuring cell-substrate tractions and cell-cell intercellular stresses utilizing traction force microscopy and monolayer stress microscopy, respectively. Our findings showed an increase in traction forces, average normal intercellular stress, maximum shear intercellular stress, and strain energy proportional to increased substrate stiffness. A substrate stiffness of 4 kPa showed 2.1 fold increase in rms tractions, 1.8 fold increase in maximum shear stress, 2.6 fold increase in average normal stress, and 1.6 fold increase in strain energy. While 11 kPa showed a 4.6 fold increase in rms tractions, 6.6 fold increase in maximum shear stress, 5.2 fold increase in average normal stress, and 2.3 fold increase in strain energy. Cell velocity, on the other hand, showed a decreasing trend with increasing stiffness. This study demonstrates for the first time that astrocytes can bear intercellular stresses and that astrocyte intercellular stresses and traction can be modified using substrate stiffness. We believe this study will be of great importance to brain pathology, specifically as it relates to treatment methods for brain tumors.
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Date Issued
2018
Identifier
CFE0007312, ucf:52126
Format
Document (PDF)
PURL
http://purl.flvc.org/ucf/fd/CFE0007312
GLIAL DIFFERENTIATION OF HUMAN UMBILICAL STEM CELLS IN 2D AND 3D ENVIRONMENTS
Title
GLIAL DIFFERENTIATION OF HUMAN UMBILICAL STEM CELLS IN 2D AND 3D ENVIRONMENTS.
Creator
Davis, Hedvika, Hickman, James, University of Central Florida
Abstract / Description
During differentiation stem cells are exposed to a range of microenvironmental chemical and physical cues. In this study, human multipotent progenitor cells (hMLPCs) were differentiated from umbilical cord into oligodendrocytes and astrocytes. Chemical cues were represented by a novel defined differentiation medium containing the neurotransmitter norepinephrine (NE). In traditional 2 dimensional (2D) conditions, the hMLPCs differentiated into oligodendrocyte precursors, but did not progress...
Show moreDuring differentiation stem cells are exposed to a range of microenvironmental chemical and physical cues. In this study, human multipotent progenitor cells (hMLPCs) were differentiated from umbilical cord into oligodendrocytes and astrocytes. Chemical cues were represented by a novel defined differentiation medium containing the neurotransmitter norepinephrine (NE). In traditional 2 dimensional (2D) conditions, the hMLPCs differentiated into oligodendrocyte precursors, but did not progress further. However, in a constructed 3 dimensional (3D) environment, the hMLPCs differentiated into committed oligodendrocytes that expressed MBP. When co-cultured with rat embryonic hippocampal neurons (EHNs), hMLPCs developed in astrocytes or oligodendrocytes, based on presence of growth factors in the differentiation medium. In co-culture, physical cues provided by axons were essential for complete differentiation of both astrocytes and oligodendrocytes. This study presents a novel method of obtaining glia from human MLPCs that could eliminate many of the difficulties associated with their differentiation from embryonic stem cells. In addition, it reveals the complex interplay between physical cues and biomolecules on stem cell differentiation.
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Date Issued
2011
Identifier
CFE0003570, ucf:48894
Format
Document (PDF)
PURL
http://purl.flvc.org/ucf/fd/CFE0003570