Regenerative Therapy for Stroke

Abstract

Stroke remains a leading cause of death and disability worldwide. An increasing number of animal studies and preclinical trials have, however, provided evidence that regenerative cell-based therapies can lead to functional recovery in stroke patients. Stem cells can differentiate into neural lineages to replace lost neurons. Moreover, they provide trophic support to tissue at risk in the penumbra surrounding the infarct area, enhance vasculogenesis, and help promote survival, migration, and differentiation of the endogenous precursor cells after stroke. Stem cells are highly migratory and seem to be attracted to areas of brain pathology such as ischemic regions. The pathotropism may follow the paradigm of stem cell homing to bone marrow and leukocytes migrating to inflammatory tissue. The molecular signaling therefore may involve various chemokines, cytokines, and integrins. Among these, stromal cell-derived factor-1 (SDF-1)/CXC chemokine receptor-4 (CXCR4) signaling is required for the interaction of stem cells and ischemia-damaged host tissues. SDF-1 is secreted primarily by bone marrow fibroblasts and is required for BMSC homing to bone marrow. Overexpression of SDF-1 in ischemic tissues has been found to enhance stem cell recruitment from peripheral blood and to induce neoangiogenesis. Furthermore, SDF-1 expression in the lesioned area peaked within 7 days postischemia, in concordance with the time window of G-CSF therapy for stroke. Recent data have shown that SDF-1 expression is directly proportional to reduced tissue oxygen tension. SDF-1 gene expression is regulated by hypoxic-inducible factor-1 (HIF-1), a hypoxia-dependent stabilization transcription factor. Thus, ischemic tissue may recruit circulating progenitors regulated by hypoxia through differential expression of HIF-lalpha and SDF-1. In addition to SDF-1, beta2-integrins also play a role in the homing of hematopoietic progenitor cells to sites of ischemia and are critical for their neovascularization capacity. In our recent report, increased expression of beta1-integrins apparently contributed to the local neovasculization of the ischemic brain as well as its functional recovery. Identification of the molecular pathways involved in stem cell homing into the ischemic areas could pave the way for the development of new treatment regimens, perhaps using small molecules, designed to enhance endogeneous mobilization of stem cells in various disease states, including chronic stroke and other neurodegenerative diseases. For maximal functional recovery, however, regenerative therapy may need to follow combinatorial approaches, which may include cell replacement, trophic support, protection from oxidative stress, and the neutralization of the growth-inhibitory components for endogenous neuronal stem cells.