In the adult brain, new neurons are continuously generated in the subventricular zone and dentate gyrus, but it is unknown whether these neurons can replace those lost following damage or disease. Here we show that stroke, caused by transient middle cerebral artery occlusion in adult rats, leads to a marked increase of cell proliferation in the subventricular zone. Stroke-generated new neurons, as well as neuroblasts probably already formed before the insult, migrate into the severely damaged area of the striatum, where they express markers of developing and mature, striatal medium-sized spiny neurons. Thus, stroke induces differentiation of new neurons into the phenotype of most of the neurons destroyed by the ischemic lesion. Here we show that the adult brain has the capacity for self-repair after insults causing extensive neuronal death. If the new neurons are functional and their formation can be stimulated, a novel therapeutic strategy might be developed for stroke in humans.

/pdf/neuronal-replacement-from-endogenous-precursors-in-the-adult-4ghf3i2h7x.pdf

Neuronal replacement from endogenous precursors in the adult brain after stroke

Malignant brain tumors strike deep into the psyche of those receiving and those delivering the diagnosis. Malignant gliomas, the most common subtype of primary brain tumors, are aggressive, highly invasive, and neurologically destructive tumors considered to be among the deadliest of human cancers. In its most aggressive manifestation, glioblastoma (GBM), median survival ranges from 9 to 12 months, despite maximum treatment efforts—a statistical fact that has changed little over several decades of technological advances in neurosurgery, radiation therapy, and clinical trials of conventional and novel therapeutics. Over the same time period, there has been an explosion of knowledge in cancer biology and basic science discovery that has fueled meaningful progress in the treatment of many common human cancers, including those of the breast, lung, and prostate. It is perplexing that therapies used effectively in the treatment of these solid tumors are overwhelmingly ineffective in the treatment of GBM, perhaps reflecting the eccentric biology and cellular origin of this neoplasm. To date, only one new agent has been documented to have modest activity against intermediate-grade gliomas, whereas no effective agents have emerged for the treatment of GBM, despite 20 years of enrolling patients in clinical trials. It is ironic that although a comprehensive view of the genetic lesions encountered in malignant gliomas has been compiled, substantive conceptual and practical barriers remain in assigning functional significance to these genetic changes and in harnessing this basic information into the development of drugs that make a difference in patient care. The history of treating malignant gliomas dates back to the middle of the 19th century and parallels landmark advances in modern surgical technique and the clinical discipline of neurology. The first brain tumor surgery of the modern era was performed in 1884 by Rickman

/pdf/malignant-glioma-genetics-and-biology-of-a-grave-matter-5dxbdiape8.pdf

Malignant glioma: Genetics and biology of a grave matter

The Evolving Concept of a Stem Cell: Entity or Function?

Widespread demyelination and axonal loss are the pathological hallmarks of multiple sclerosis. The multifocal nature of this chronic inflammatory disease of the central nervous system complicates cellular therapy and puts emphasis on both the donor cell origin and the route of cell transplantation. We established syngenic adult neural stem cell cultures and injected them into an animal model of multiple sclerosis--experimental autoimmune encephalomyelitis (EAE) in the mouse--either intravenously or intracerebroventricularly. In both cases, significant numbers of donor cells entered into demyelinating areas of the central nervous system and differentiated into mature brain cells. Within these areas, oligodendrocyte progenitors markedly increased, with many of them being of donor origin and actively remyelinating axons. Furthermore, a significant reduction of astrogliosis and a marked decrease in the extent of demyelination and axonal loss were observed in transplanted animals. The functional impairment caused by EAE was almost abolished in transplanted mice, both clinically and neurophysiologically. Thus, adult neural precursor cells promote multifocal remyelination and functional recovery after intravenous or intrathecal injection in a chronic model of multiple sclerosis.

Injection of adult neurospheres induces recovery in a chronic model of multiple sclerosis

Because neurogenesis persists in the adult mammalian brain and can be regulated by physiological and pathological events, we investigated its possible involvement in the brain's response to focal cerebral ischemia. Ischemia was induced by occlusion of the middle cerebral artery in the rat for 90 min, and proliferating cells were labeled with 5-bromo-2'-deoxyuridine-5'-monophosphate (BrdUrd) over 2-day periods before sacrificing animals 1, 2 or 3 weeks after ischemia. Ischemia increased the incorporation of BrdUrd into cells in two neuroproliferative regions-the subgranular zone of the dentate gyrus and the rostral subventricular zone. Both effects were bilateral, but that in the subgranular zone was more prominent on the ischemic side. Cells labeled with BrdUrd coexpressed the immature neuronal markers doublecortin and proliferating cell nuclear antigen but did not express the more mature cell markers NeuN and Hu, suggesting that they were nascent neurons. These results support a role for ischemia-induced neurogenesis in what may be adaptive processes that contribute to recovery after stroke.

https://www.pnas.org/content/pnas/98/8/4710.full.pdf

Neurogenesis in dentate subgranular zone and rostral subventricular zone after focal cerebral ischemia in the rat

One of the impediments to the treatment of brain tumors (e.g., gliomas) has been the degree to which they expand, infiltrate surrounding tissue, and migrate widely into normal brain, usually rendering them “elusive” to effective resection, irradiation, chemotherapy, or gene therapy. We demonstrate that neural stem cells (NSCs), when implanted into experimental intracranial gliomas in vivo in adult rodents, distribute themselves quickly and extensively throughout the tumor bed and migrate uniquely in juxtaposition to widely expanding and aggressively advancing tumor cells, while continuing to stably express a foreign gene. The NSCs “surround” the invading tumor border while “chasing down” infiltrating tumor cells. When implanted intracranially at distant sites from the tumor (e.g., into normal tissue, into the contralateral hemisphere, or into the cerebral ventricles), the donor cells migrate through normal tissue targeting the tumor cells (including human glioblastomas). When implanted outside the CNS intravascularly, NSCs will target an intracranial tumor. NSCs can deliver a therapeutically relevant molecule—cytosine deaminase—such that quantifiable reduction in tumor burden results. These data suggest the adjunctive use of inherently migratory NSCs as a delivery vehicle for targeting therapeutic genes and vectors to refractory, migratory, invasive brain tumors. More broadly, they suggest that NSC migration can be extensive, even in the adult brain and along nonstereotypical routes, if pathology (as modeled here by tumor) is present.

https://www.pnas.org/content/pnas/97/23/12846.full.pdf

Neural stem cells display extensive tropism for pathology in adult brain: evidence from intracranial gliomas.

Multipotent neural progenitors and stem cells may integrate appropriately into the developing and degenerating central nervous system. They may also be effective in the replacement of genes, cells, and nondiffusible factors in either a widespread or a more circumscribed manner, depending on the therapeutic demands of the clinical situation. In addition, they may be uniquely responsive to some types of neurodegenerative conditions. We believe that these various appealing capabilities are the normal expression of basic biologic properties and attributes of a stem cell. The therapeutic utility of some of those properties is illustrated in this review of ongoing work in our laboratory, particularly with regard to spinal dysfunction. In these examples, we believe we have tapped into a mechanism that underlies a remarkable degree of natural plasticity programmed into the nervous system at the cellular level, and we have now exploited those properties for therapeutic ends.

Transplantation of neural progenitor and stem cells: Developmental insights may suggest new therapies for spinal cord and other CNS dysfunction

Potential of neural "stem-like" cells for gene therapy and repair of the degenerating central nervous system.

When neural progenitors are immortalized, they appear in many ways to behave as neural stem cells In fact, they have been called “stem-like cells” We have demonstrated that immortalized, multipotent, clonal neural progenitors or stem-like cells can, following transplantation, integrate appropriately into recipient mouse nervous system (from embryo to adult) and differentiate into a range of neurons and glia throughout the neuraxis Donor progenitors appear to intermingle nondisruptively with endogenous progenitors and respond to many of the same spatial and temporal developmental signals in the same manner as host progenitors Immortalization does not abrogate their ability to respond to normal cues (eg withdraw from the cell cycle, differentiate, intract with host cells) Because engrafted progenitors are recognized by expression of retrovirally/transduced lacZ, these data also support the feasibility of transplanting neural stem-like cells — expressing genes of developmental or therapeutic importance (either intrinsically or following ex vivo genetic manipulation) — as a strategy for sustained delivery of such factors directly to the CNS as integral members of the cytoarchitecture Furthermore, progenitors might also replace injured cells and/or provide nondiffusible factors (myelin, “bridges,” cell-cell contact signals, extracellular matrix) that might allow the injured host to reform its own connections Some of our studies have suggested successful therapeutic gene expression throughout the brains of mouse models of genetic metabolic neurodegenerative disease; repletion of degenerated or developmentally impaired neurons in new-born and adult mouse cerebrum and spinal cord; and differentiation into oligodendroglia that improve myelination in mouse mutants with diffuse white matter disease We suggest that the inherent biologic properties of neural progenitors make them appealingly suited to be efficient, multifaceted vehicles for cell replacement, repair, and gene transfer in CNS dysfuncion Their apparent ability to address widespread neuropathology is intriguing because most neurologic disease is not focal, but rather multifocal or global The use of neural stem-like cells may, therefore, allow a cellular therapy like transplantation to address those therapeutic challenges usually consigned to pharmacologic or genetic interventions Such stem-like cell lines may also provide models for the study of the commitment, differentation, and plasticity of neural progenitors and stem cells We have hypothesized that some multipotent neural stem cells may have intrinsic ferentiation programs that may nevertheless be influenced by appropriately timed microenvironmental factors Therefore, a system such as this may facilitate exploration of the reciprocal interactions between external cues and instrinsic programs

Shaoxiong Liu

Papers

Neural stem cells display extensive tropism for pathology in adult brain: evidence from intracranial gliomas.

Transplantation of neural progenitor and stem cells: Developmental insights may suggest new therapies for spinal cord and other CNS dysfunction

Potential of neural "stem-like" cells for gene therapy and repair of the degenerating central nervous system.

Transplantation and Differentiation of Neural “Stem-Like” Cells: Possible Insights Into Development and Therapeutic Potential