Transplanted multipotential neural precursor cells migrate into the inflamed white matter in response to experimental autoimmune encephalomyelitis

Abstract

Transplanted neural precursor cells remyelinate efficiently acutely demyelinated focal lesions. However, the clinical value of cell transplantation in a chronic, multifocal disease like multiple sclerosis will depend on the ability of transplanted cells to migrate to the multiple disease foci in the brain. Here, we expanded newborn rat neural precursor cells in spheres and transplanted them intracerebroventricularly or intrathecally in rats. The cells were labeled by the nuclear fluorescent dye Hoechst or by incubation with BrdU to enable their identification at 2 days and 2 weeks after transplantation, respectively. Spheres consisted of PSA-NCAM(+), nestin(+), NG2(-) undifferentiated precursor cells that differentiated in vitro into astrocytes, oligodendrocytes, and neurons. Spheres that were transplanted into intact rats remained mostly in the ventricles or in the spinal subarachnoid space. Following transplantation at peak of experimental autoimmune encephalomyelitis, cells migrated into the brain or spinal cord parenchyma, exclusively into inflamed white matter but not into adjacent gray matter regions. After 2 weeks, many transplanted cells had migrated into distant white matter tracts and acquired specific markers of the astroglial and oligodendroglial lineages. Thus, the inflammatory process may attract targeted migration of transplanted precursor cells into the brain parenchyma.

Transplantation of neural progenitors enhances production of endogenous cells in the impaired brain

“…27 Isolation of neural precursors and growth of neurospheres. This procedure is based on the studies of Ben-Hur et al 28,29 For the derivation of neural progenitors, newborn (PN1-PN2) HS/Ibg mice were used. Cerebral cortices were minced, digested in 0.025% trypsin for 20 min and dissociated with a 5 ml Sphere transplantation.…”

Cell Therapy for Multiple Sclerosis

“…Recruitment and mobilization of OPCs and multipotential neural precursors in the models of MS have been mainly attributed to the inflammatory process. Brain inflammation attracts the migration of both endogenous [57] and transplanted [94][95][96][97] precursor cells. Various inflammatory cytokines can induce neural/oligodendrocyte precursor cell migration.…”

“…Expression of PSA-NCAM on the cell membrane has been associated with stem cell commitment to neuronal or glial fate, depending on time and place in development [135][136][137]. Indeed, such PSA-NCAM+ glial precursors, growing as neurospheres and also termed as oligospheres [135,138], efficiently myelinated the brains of shi mice [138][139][140], remyelinated 95 to 100% of axons following local injection into the dorsal columns of rats [141], and efficiently migrated along inflamed white matter tracts of rats with EAE [94,95]. Similarly, adult human SVZ precursors remyelinated the adult rat spinal cord [142].…”

“…The inflammatory process in the CNS of EAE animals was found to be a powerful stimulus stimulating subventricular PSA-NCAM+ cells [56,57] and attracting targeted migration of transplanted neural and oligodendroglial precursor cells [94,95,257]. Following ICV transplantation of neurospheres, cells migrated into inflamed periventricular white matter tracts, and differentiated mainly into glial progeny.…”

HIV-1, chemokines and neurogenesis

“…Furthermore, it has been shown that stimulated neurogenesis occurs in the brains of rodent models of epilepsy, stroke, trauma, Alzheimer's, Parkinson's and Huntington's diseases (Parent, 2003). In demyelinating disease models, such as an experimental autoimmune encephalomyelitis (EAE), an animal model of MS, progenitors primarily form oligodendrocytes and remyelinate damaged white matter (Picard-Riera et al, 2002;Ben-Hur et al, 2003;Pluchino et al, 2003).…”