Neural stem cells exist not only in the developing mammalian nervous system but also in the adult nervous system of all mammalian organisms, including humans. Neural stem cells can also be derived from more primitive embryonic stem cells. The location of the adult stem cells and the brain regions to which their progeny migrate in order to differentiate remain unresolved, although the number of viable locations is limited in the adult. The mechanisms that regulate endogenous stem cells are poorly understood. Potential uses of stem cells in repair include transplantation to repair missing cells and the activation of endogenous cells to provide "self-repair. " Before the full potential of neural stem cells can be realized, we need to learn what controls their proliferation, as well as the various pathways of differentiation available to their daughter cells.

https://science.sciencemag.org/content/sci/287/5457/1433.full.pdf

Mammalian neural stem cells.

s, and 360 patents, and edited 12 books. He has also received over 80 major awards including the Gairdner Foundation International Award, Lemelson-MIT prize, ACS’s Applied Polymer Science and Polymer Chemistry Awards, AICHE’s Professional Progress, Bioengineering, Walker and Stine Materials Science and Engineering Awards. In 1989, Dr. Langer was elected to the Institute of Medicine of the National Academy of Sciences, and in 1992 he was elected to both the National Academy of Engineering and the National Academy of Sciences. He is the only active member of all three National Academies. Kevin Shakesheff was born in Ashington, Northumberland, U.K., in 1969. He received his Bacheclor of Pharmacy degree from the University of Nottingham in 1991 and a Ph.D. from the same institution in 1995. In 1996 he became a NATO Postdoctoral Fellow at MIT, Department of Chemical Engineering. He is currently an EPSRC Advanced Fellow at the School of Pharmaceutical Sciences, The University of Nottingham. His research group investigates new methods of engineering polymer surfaces and the application of these engineered materials in drug delivery and tissue engineering. 3182 Chemical Reviews, 1999, Vol. 99, No. 11 Uhrich et al.

Polymeric Systems for Controlled Drug Release

Transformed stem cells have been isolated from some human cancers. We report that, unlike other brain cancers, the lethal glioblastoma multiforme contains neural precursors endowed with all of the critical features expected from neural stem cells. Similar, yet not identical, to their normal neural stem cell counterpart, these precursors emerge as unipotent (astroglial) in vivo and multipotent (neuronal-astroglial-oligodendroglial) in culture. More importantly, these cells can act as tumor-founding cells down to the clonal level and can establish tumors that closely resemble the main histologic, cytologic, and architectural features of the human disease, even when challenged through serial transplantation. Thus, cells possessing all of the characteristics expected from tumor neural stem cells seem to be involved in the growth and recurrence of adult human glioblastomas multiforme.

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Isolation and Characterization of Tumorigenic, Stem-like Neural Precursors from Human Glioblastoma

The remarkable developmental potential and replicative capacity of human embryonic stem (ES) cells promise an almost unlimited supply of specific cell types for transplantation therapies. Here we describe the in vitro differentiation, enrichment, and transplantation of neural precursor cells from human ES cells. Upon aggregation to embryoid bodies, differentiating ES cells formed large numbers of neural tube-like structures in the presence of fibroblast growth factor 2 (FGF-2). Neural precursors within these formations were isolated by selective enzymatic digestion and further purified on the basis of differential adhesion. Following withdrawal of FGF-2, they differentiated into neurons, astrocytes, and oligodendrocytes. After transplantation into the neonatal mouse brain, human ES cell-derived neural precursors were incorporated into a variety of brain regions, where they differentiated into both neurons and astrocytes. No teratoma formation was observed in the transplant recipients. These results depict human ES cells as a source of transplantable neural precursors for possible nervous system repair.

http://digital.library.ucla.edu/websites/2004_996_027/ntp.neuroscience.wisc.edu/faculty/fac-art/zhangb.pdf

In vitro differentiation of transplantable neural precursors from human embryonic stem cells

Stem cells, which are clonogenic cells with self-renewal and multilineage differentiation properties, have the potential to replace or repair damaged tissue. We have directly isolated clonogenic human central nervous system stem cells (hCNS-SC) from fresh human fetal brain tissue, using antibodies to cell surface markers and fluorescence-activated cell sorting. These hCNS-SC are phenotypically 5F3 (CD133)+, 5E12+, CD34−, CD45−, and CD24−/lo. Single CD133+ CD34− CD45− sorted cells initiated neurosphere cultures, and the progeny of clonogenic cells could differentiate into both neurons and glial cells. Single cells from neurosphere cultures initiated from CD133+ CD34− CD45− cells were again replated as single cells and were able to reestablish neurosphere cultures, demonstrating the self-renewal potential of this highly enriched population. Upon transplantation into brains of immunodeficient neonatal mice, the sorted/expanded hCNS-SC showed potent engraftment, proliferation, migration, and neural differentiation.

https://www.pnas.org/content/pnas/97/26/14720.full.pdf

Direct isolation of human central nervous system stem cells

In vitro expansion of a multipotent population of human neural progenitor cells.

Background: Seizures occur after the diagnosis of brain tumors in up to 40% of patients. Prophylactic anticonvulsants are widely advocated despite a lack of convincing evidence of their efficacy in preventing first seizures. We conducted a randomized, double-blind, placebo-controlled study comparing the incidence of first seizures in divalproex sodium- and placebo-treated patients with newly diagnosed brain tumors. Patients and Methods: Patients who had not previously had a seizure were randomized within 14 days of diagnosis of their brain tumor to receive either divalproex sodium or placebo. All patients had at least one supratentorial brain lesion, a Karnofsky Performance Score (KPS) more than equals 50%, and no previous anticonvulsant use or other brain disease. Compliance and adequacy of dosing were assessed by pill counts and monthly blood levels. Results: Seventy-four of 75 consecutive eligible patients were entered in this study. Median follow-up was 7 months. The drug and placebo groups did not differ significantly in age, sex, KPS, primary tumor type, number or location of brain lesions, frequency of brain surgery, or pretreatment EEG. Thirteen of 37 patients (35%) receiving divalproex sodium and 9 of 37 patients (24%) on placebo had seizures. The odds ratio for a seizure in the divalproex sodium arm relative to the placebo arm was 1.7 (95% CI 0.6 to 4.6; p equals 0.3). The hypothesis that anticonvulsant prophylaxis provides a reduction in the frequency of first seizure as small as 30% was rejected (p equals 0.05). Conclusions: Anticonvulsant prophylaxis with divalproex sodium is not indicated for patients with brain tumors who have not had seizures. NEUROLOGY 1996;46: 985-991.

A randomized, blinded, placebo-controlled trial of divalproex sodium prophylaxis in adults with newly diagnosed brain tumors

Living cells such as animal cells which produce biologically active factors are encapsulated within a semipermeable, polymeric membrane such as polyacrylate by co-extruding an aqueous cell suspension and a polymeric solution through a common port having at least one concentric bores to form a tubular extrudate having a polymeric membrane which encapsulates the cell suspension. The cell suspension is extruded through an inner bore and the polymeric solution is extruded through an outer bore while a pressure differential is maintained between the cell suspension and the polymeric solution to impede solvent diffusion from the polymeric solution into the cell suspension. The polymeric solution coagulates to form an outer coating or membrane as the polymeric solution and the cell suspension are extruded through the extrusion port. As the outer membrane is formed, the ends of the tubular extrudate are sealed to form a cell capsule. In one embodiment, the tubular extrudate is sealed at intervals to define separate cell compartments connected by polymeric links. In another embodiment, a cell capsule connected to a tethering filament is formed. The polymeric membrane may contain additives such as a surfactant, an anti-inflammatory agent or an anti-oxidant and can be coated with a protective barrier. The cell suspension may contain nutrients and an anchorage substrate.

Cell culture-containing tubular capsule produced by co-extrusion

https://www.rug.nl/research/pathology/medbiol/pdf/orivetip2015.pdf

Lars Wahlberg

Papers

In vitro expansion of a multipotent population of human neural progenitor cells.

A randomized, blinded, placebo-controlled trial of divalproex sodium prophylaxis in adults with newly diagnosed brain tumors

Cell culture-containing tubular capsule produced by co-extrusion

Cell encapsulation: technical and clinical advances.

Encapsulated cell biodelivery of GDNF: A novel clinical strategy for neuroprotection and neuroregeneration in Parkinson's disease?