Persistent Production of Neurons from Adult Brain Stem Cells During Recovery after Stroke

Abstract

Neural stem cells in the subventricular zone of adult rodents produce new striatal neurons that may replace those that have died after stroke; however, the neurogenic response has been considered acute and transient, yielding only small numbers of neurons. In contrast, we show herein that striatal neuroblasts are generated without decline at least for 4 months after stroke in adult rats. Neuroblasts formed early or late after stroke either differentiate into mature neurons, which survive for several months, or die through caspasemediated apoptosis. The directed migration of the new neurons toward the ischemic damage is regulated by stromal cell-derived factor-1␣ and its receptor CXCR4. These results show that endogenous neural stem cells continuously supply the injured adult brain with new neurons, which suggests novel self-repair strategies to improve recovery after stroke. STEM CELLS 2006;24:739 -747

Brain injury activates microglia that induce neural stem cell proliferation ex vivo and promote differentiation of neurosphere-derived cells into neurons and oligodendrocytes

“…Moreover, the enhanced (3-to 4-fold) neuronal differentiation of NSPCs that we observed among cells derived from neurospheres harvested from injured brains is consistent with previous observations showing increased neurogenesis in vivo following these brain lesions (Arvidsson et al, 2002, Tattersfield et al, 2004, Zhang et al, 2004b. Interestingly, this stroke-induced neurogenesis in the SVZ is concomitant with trophic microglial cells expressing insulin-like growth factor-1 in the vicinity of the SVZ (Thored et al, 2006). In addition, these neurospheres generated higher numbers of oligodendrocytes in line with previous studies reporting an increased density of oligodendrocytes following focal ischemia in the rat (Gregersen et al, 2001).…”

“…Enhanced neurogenesis has been suggested to occur in stroke patients (Jin et al, 2006, Macas et al, 2006. The notion that enhanced proliferation of NSPCs following stroke promotes functional recovery (Nygren et al, 2006, Thored et al, 2006) makes these findings potentially clinically relevant. The ambiguous response of microglia (pro-/anti-inflammatory) to injury depends on the types of stimulus (Hanisch and Kettenmann, 2007) and receptor activation (Ribes et al, 2009),…”

CXCR4 signaling in the regulation of stem cell migration and development

“…These neural progenitors, which can be expanded in cell culture, also express chemokine receptors and so can "home" to sites of chemokine production in the brain (Tran et al, 2004). In support of such possibilities it has been observed that both CCR2 (Liu et al, 2007) and CXCR4 (Ohab et al, 2006;Thored et al, 2006) expressing progenitors are found within stroke induced lesions in the brain and that interference with chemokine signaling blocks this recruitment (Belmadani et al, 2006;Ohab et al, 2006). The migration of neural progenitors is not only required for brain repair in the context of neurodegeneration but is also important in brain repair as the result of demyelination.…”

The Rho Kinase Pathway Regulates Mouse Adult Neural Precursor Cell Migration

“…Ischemic stroke induced neurogenesis in the rodent SVZ [1,72,73] and stimulated newborn precursor migration to the peri-infarct regions [74,75]. This migration may be induced by SDF-1/CXCL4, which plays a role in directing newborn neurons toward an ischemic lesion [76] and may be enhanced by release of mitogenic factors, such as EGF [77,78].…”