Adult neural stem cells: response to stroke injury and potential for therapeutic applications

Abstract

The plasticity of neural stem/progenitor cells allows a variety of different responses to many environmental cues. In the past decade, significant research has gone into understanding the regulation of neural stem/progenitor cell properties, because of their promise for cell replacement therapies in adult neurological diseases. Both endogenous and grafted neural stem/progenitor cells are known to have the ability to migrate long distances to lesioned sites after brain injury and differentiate into new neurons. Several chemokines and growth factors, including stromal cell-derived factor-1 and vascular endothelial growth factor, have been shown to stimulate the proliferation, differentiation, and migration of neural stem/progenitor cells, and investigators have now begun to identify the critical downstream effectors and signaling mechanisms that regulate these processes. Both our own lab and others have shown that the extracellular matrix and matrix remodeling factors play a critical role in directing cell differentiation and migration of adult neural stem/progenitor cells within injured sites. Identification of these and other molecular pathways involved in stem cell homing into ischemic areas is vital for the development of new treatments. To ensure the best functional recovery, regenerative therapy may require the application of a combination approach that includes cell replacement, trophic support, and neural protection. Here we review the current state of our knowledge about endogenous adult and exogenous neural stem/progenitor cells as potential therapeutic agents for central nervous system injuries.

Figure 1. Potential roles of MMPs in adult NSPC migration and differentiation

1) Extracellular chemokines, such as SDF-1, from either the surrounding niche within a normal brain or an injured region, signal the activation of MMP-3 and MMP-9. 2) MMPs can be secreted locally to promote the breakdown of the ECM and drive the migration and differentiation of the NSPC toward the concentration gradient of chemokines. 3) MMP can cleave cell surface proteins, such as integrins and cadherins, to stimulate a signaling cascade to activate the pathways for migration and differentiation of NSPCs. 4) MMP-3 and MMP-9 have been suggested to cleave intracellular proteins that participate in the formation of transcriptional complexes or degrading protein inhibitors, which will drive the expression of specific genes involved in the migration and differentiation of NSPCs.

Figure 2. Potential of stem cells for cell-based therapies for brain injuries

1) Growth factors and gene therapies can potentially be used to instruct either endogenous adult NSPCs or transplanted stem cells to repair the injured brain. 2) Cells might be isolated from patient tissues (e.g., biopsied from brain, skin, or blood), and these cells then differentiated into either NSPCs or neurons that are used for autologously grafting into an individual patients. 3) Both embryonic stem cells (ES cells, derived from fertilized embryos) and induced pluripotent stem cells (iPS cells, reprogrammed from patient somatic cells to prevent graft rejection) can be directed to generate NSPCs (dotted lines), which can then be used for transplantation. 4) Like NSPCs, ES cells and iPS cells can be differentiated into young neurons; however, how to direct differentiation into pure and specific types of new neurons remains unknown. 5) Other studies have focused on grafting specific types of neurons or an intermediate cell population (precursor to the desired cell type) to replace lost neurons by directed differentiation of different types of stem cells (such as CD34⁺ or HSC). Finally, it is important to determine whether a combination of gene therapy and cell transplantation will further enhance brain repair and the recovery of function for patients.