Adult neural stem/progenitor cells in response to their microenvironment: Proliferation, differentiation and migration

The plasticity of adult neural stem/progenitor cells allows a differential response to a variety of environmental cues. Over the past decade, significant research efforts have been devoted into understanding the regulation of neural stem/progenitor cells due to their promising potential for cell replacement therapies in adult neurological diseases. It has been demonstrated that after brain injury both endogenous and grafted neural stem/progenitor cells have the ability to proliferate to expand their number, migrate long distances to the lesioned site and differentiate into new specific neurons to replace the ones that have been lost. All these procedure are regulated by extrinsic cue found in the microenvironment surrounding the neural stem/progenitor cells. Several chemokines and growth factors have been identified that stimulate the proliferation, differentiation, and migration of endogenous or exogenous neural stem/progenitor cells. The first part of this dissertation work (Chapter 5) identifies the role of several extrinsic factors expressed and secreted by hippocampal astrocytes that regulate the neuronal differentiation of adult neural stem/progenitor cells in the neurogenic region of the dentate gyrus. While in non-neurogenic regions, astrocytes secrete factors that inhibit the differentiation of adult neural stem/progenitor cells.;Cell migration is an essential component of neurogenesis in both embryonic and adult brains. Many critical signaling factors and molecules are involved in governing the dynamic process of cell migration, which includes chemotaxis, cytoskeleton restructuring, nuclear translocation, and extracellular matrix remodeling. Extracellular molecules regulate the interaction and communication of the cell with its microenvironment. Investigators have shown that extracellular matrix and matrix remodeling factors play a critical role in directing stem cell migration during development and in the response to brain injury. Identification the molecular pathways and mechanisms of these factors, involved in regulating stem cell fate choice and homing into the damaged areas is vital for new treatments in brain injury. The second part of this dissertaition (Chapter 6), I focus on demonstrating that several matrix metalloproteinases are demonstrated to play a role in both the migration and differentiation of adult neural stem cells/progenitor in response to stroke-induced chemokines. The role of matrix metalloproteinase in differentiation may be the first evidence of extracellular molecules effecting the intrinsic regulation of adult neural stem/progenitor fate choice.