Neural stem cells (NSCs) are self-renewing, multipotent cells that firstly generate the radial glial progenitor cells that generate the neurons and glia of the nervous system of all animals during embryonic development. Some neural progenitor stem cells persist in highly restricted regions in the adult vertebrate brain and continue to produce neurons throughout life.
Stem cells are characterized by their capacity to differentiate into multiple cell types. They undergo symmetric or asymmetric cell division into two daughter cells. In symmetric cell division, both daughter cells are also stem cells. In asymmetric division, a stem cell produces one stem cell and one specialized cell. NSCs primarily differentiate into neurons, astrocytes, and oligodendrocytes.
There are two basic types of stem cell: adult stem cells, which are limited in their ability to differentiate, and embryonic stem cells (ESCs), which are pluripotent and have the capability of differentiating into any cell type.
Neural stem cells are more specialized than ESCs because they only generate radial glial cells that give rise to the neurons and to glia of the central nervous system (CNS). During the embryonic development of vertebrates, NSCs transition into radial glial cells (RGCs) also known as radial glial progenitor cells, (RGPs) and reside in a transient zone called the ventricular zone (VZ). Neurons are generated in large numbers by (RPGs) during a specific period of embryonic development through the process of neurogenesis, and continue to be generated in adult life in restricted regions of the adult brain. Adult NSCs differentiate into new neurons within the adult subventricular zone (SVZ), a remnant of the embryonic germinal neuroepithelium, as well as the dentate gyrus of the hippocampus.
Adult NSCs were first isolated from mouse striatum in the early 1990s. They are capable of forming multipotent neurospheres when cultured in vitro. Neurospheres can produce self-renewing and proliferating specialized cells. These neurospheres can differentiate to form the specified neurons, glial cells, and oligodendrocytes. In previous studies, cultured neurospheres have been transplanted into the brains of immunodeficient neonatal mice and have shown engraftment, proliferation, and neural differentiation.
NSCs are stimulated to begin differentiation via exogenous cues from the microenvironment, or stem cell niche. Some neural cells are migrated from the SVZ along the rostral migratory stream which contains a marrow-like structure with ependymal cells and astrocytes when stimulated. The ependymal cells and astrocytes form glial tubes used by migrating neuroblasts. The astrocytes in the tubes provide support for the migrating cells as well as insulation from electrical and chemical signals released from surrounding cells. The astrocytes are the primary precursors for rapid cell amplification. The neuroblasts form tight chains and migrate towards the specified site of cell damage to repair or replace neural cells. One example is a neuroblast migrating towards the olfactory bulb to differentiate into periglomercular or granule neurons which have a radial migration pattern rather than a tangential one.
Neural stem cell proliferation declines as a consequence of aging. Various approaches have been taken to counteract this age-related decline. Because FOX proteins regulate neural stem cell homeostasis, FOX proteins have been used to protect neural stem cells by inhibiting Wnt signaling.
Epidermal growth factor (EGF) and fibroblast growth factor (FGF) are mitogens that promote neural progenitor and stem cell growth in vitro, though other factors synthesized by the neural progenitor and stem cell populations are also required for optimal growth. It is hypothesized that neurogenesis in the adult brain originates from NSCs. The origin and identity of NSCs in the adult brain remain to be defined.
The most widely accepted model of an adult NSC is a radial, astrocytes-like, GFAP-positive cell. Quiescent stem cells are Type B that are able to remain in the quiescent state due to the renewable tissue provided by the specific niches composed of blood vessels, astrocytes, microglia, ependymal cells, and extracellular matrix present within the brain. These niches provide nourishment, structural support, and protection for the stem cells until they are activated by external stimuli. Once activated, the Type B cells develop into Type C cells, active proliferating intermediate cells, which then divide into neuroblasts consisting of Type A cells. The undifferentiated neuroblasts form chains that migrate and develop into mature neurons. In the olfactory bulb, they mature into GABAergic granule neurons, while in the hippocampus they mature into dentate granule cells.
NSCs have an important role during development producing the enormous diversity of neurons, astrocytes and oligodendrocytes in the developing CNS. They also have important role in adult animals, for instance in learning and hippocampal plasticity in the adult mice in addition to supplying neurons to the olfactory bulb in mice.
Notably the role of NSCs during diseases is now being elucidated by several research groups around the world. The responses during stroke, multiple sclerosis, and Parkinson's disease in animal models and humans is part of the current investigation. The results of this ongoing investigation may have future applications to treat human neurological diseases.
Neural stem cells have been shown to engage in migration and replacement of dying neurons in classical experiments performed by Sanjay Magavi and Jeffrey Macklis. Using a laser-induced damage of cortical layers, Magavi showed that SVZ neural progenitors expressing Doublecortin, a critical molecule for migration of neuroblasts, migrated long distances to the area of damage and differentiated into mature neurons expressing NeuN marker. In addition Masato Nakafuku's group from Japan showed for the first time the role of hippocampal stem cells during stroke in mice. These results demonstrated that NSCs can engage in the adult brain as a result of injury. Furthermore, in 2004 Evan Y. Snyder's group showed that NSCs migrate to brain tumors in a directed fashion. Jaime Imitola, M.D and colleagues from Harvard demonstrated for the first time, a molecular mechanism for the responses of NSCs to injury. They showed that chemokines released during injury such as SDF-1a were responsible for the directed migration of human and mouse NSCs to areas of injury in mice. Since then other molecules have been found to participate in the responses of NSCs to injury. All these results have been widely reproduced and expanded by other investigators joining the classical work of Richard L. Sidman in autoradiography to visualize neurogenesis during development, and neurogenesis in the adult by Joseph Altman in the 1960s, as evidence of the responses of adult NSCs activities and neurogenesis during homeostasis and injury.
The search for additional mechanisms that operate in the injury environment and how they influence the responses of NSCs during acute and chronic disease is matter of intense research.
Cell death is a characteristic of acute CNS disorders as well as neurodegenerative disease. The loss of cells is amplified by the lack of regenerative abilities for cell replacement and repair in the CNS. One way to circumvent this is to use cell replacement therapy via regenerative NSCs. NSCs can be cultured in vitro as neurospheres. These neurospheres are composed of neural stem cells and progenitors (NSPCs) with growth factors such as EGF and FGF. The withdrawal of these growth factors activate differentiation into neurons, astrocytes, or oligodendrocytes which can be transplanted within the brain at the site of injury. The benefits of this therapeutic approach have been examined in Parkinson's disease, Huntington's disease, and multiple sclerosis. NSPCs induce neural repair via intrinsic properties of neuroprotection and immunomodulation. Some possible routes of transplantation include intracerebral transplantation and xenotransplantation.
An alternative therapeutic approach to the transplantation of NSPCs is the pharmacological activation of endogenous NSPCs (eNSPCs). Activated eNSPCs produce neurotrophic factors, several treatments that activate a pathway that involves the phosphorylation of STAT3 on the serine residue and subsequent elevation of Hes3 expression (STAT3-Ser/Hes3 Signaling Axis) oppose neuronal death and disease progression in models of neurological disorder.
Human midbrain-derived neural progenitor cells (hmNPCs) have the ability to differentiate down multiple neural cell lineages that lead to neurospheres as well as multiple neural phenotypes. The hmNPC can be used to develop a 3D in vitro model of the human CNS. There are two ways to culture the hmNPCs, the adherent monolayer and the neurosphere culture systems. The neurosphere culture system has previously been used to isolate and expand CNS stem cells by its ability to aggregate and proliferate hmNPCs under serum-free media conditions as well as with the presence of epidermal growth factor (EGF) and fibroblast growth factor-2 (FGF2). Initially, the hmNPCs were isolated and expanded before performing a 2D differentiation which was used to produce a single-cell suspension. This single-cell suspension helped achieve a homogenous 3D structure of uniform aggregate size. The 3D aggregation formed neurospheres which was used to form an in vitro 3D CNS model.
Traumatic brain injury (TBI) can deform the brain tissue, leading to necrosis primary damage which can then cascade and activate secondary damage such as excitotoxicity, inflammation, ischemia, and the breakdown of the blood-brain-barrier. Damage can escalate and eventually lead to apoptosis or cell death. Current treatments focus on preventing further damage by stabilizing bleeding, decreasing intracranial pressure and inflammation, and inhibiting pro-apoptoic cascades. In order to repair TBI damage, an upcoming therapeutic option involves the use of NSCs derived from the embryonic peri-ventricular region. Stem cells can be cultured in a favorable 3-dimensional, low cytotoxic environment, a hydrogel, that will increase NSC survival when injected into TBI patients. The intracerebrally injected, primed NSCs were seen to migrate to damaged tissue and differentiate into oligodendrocytes or neuronal cells that secreted neuroprotective factors.
Galectin-1 is expressed in adult NSCs and has been shown to have a physiological role in the treatment of neurological disorders in animal models. There are two approaches to using NSCs as a therapeutic treatment: (1) stimulate intrinsic NSCs to promote proliferation in order to replace injured tissue, and (2) transplant NSCs into the damaged brain area in order to allow the NSCs to restore the tissue. Lentivirus vectors were used to infect human NSCs (hNSCs) with Galectin-1 which were later transplanted into the damaged tissue. The hGal-1-hNSCs induced better and faster brain recovery of the injured tissue as well as a reduction in motor and sensory deficits as compared to only hNSC transplantation.
Neural stem cells are routinely studied in vitro using a method referred to as the Neurosphere Assay (or Neurosphere culture system), first developed by Reynolds and Weiss. Neurospheres are intrinsically heterogeneous cellular entities almost entirely formed by a small fraction (1 to 5%) of slowly dividing neural stem cells and by their progeny, a population of fast-dividing nestin-positive progenitor cells. The total number of these progenitors determines the size of a neurosphere and, as a result, disparities in sphere size within different neurosphere populations may reflect alterations in the proliferation, survival and/or differentiation status of their neural progenitors. Indeed, it has been reported that loss of 1-integrin in a neurosphere culture does not significantly affect the capacity of 1-integrin deficient stem cells to form new neurospheres, but it influences the size of the neurosphere: 1-integrin deficient neurospheres were overall smaller due to increased cell death and reduced proliferation.
While the Neurosphere Assay has been the method of choice for isolation, expansion and even the enumeration of neural stem and progenitor cells, several recent publications have highlighted some of the limitations of the neurosphere culture system as a method for determining neural stem cell frequencies. In collaboration with Reynolds, STEMCELL Technologies has developed a collagen-based assay, called the Neural Colony-Forming Cell (NCFC) Assay, for the quantification of neural stem cells. Importantly, this assay allows discrimination between neural stem and progenitor cells.
The first evidence that neurogenesis occurs in certain regions of the adult mammalian brain came from [3H]-thymidine labeling studies conducted by Altman and Das in 1965 which showed postnatal hippocampal neurogensis in young rats. In 1989, Sally Temple described multipotent, self-renewing progenitor and stem cells in the subventricular zone (SVZ) of the mouse brain. In 1992, Brent A. Reynolds and Samuel Weiss were the first to isolate neural progenitor and stem cells from the adult striatal tissue, including the SVZ one of the neurogenic areas of adult mice brain tissue. In the same year the team of Constance Cepko and Evan Y. Snyder were the first to isolate multipotent cells from the mouse cerebellum and stably transfected them with the oncogene v-myc. This molecule is one of the genes widely used now to reprogram adult non-stem cells into pluripotent stem cells. Since then, neural progenitor and stem cells have been isolated from various areas of the adult central nervous system, including non-neurogenic areas, such as the spinal cord, and from various species including humans.
Intensity-modulated radiation to spare neural stem cells in brain tumors: a computational platform for evaluation of physical and biological dose metrics. Jaganathan A, Tiwari M, Phansekar R, Panta R, Huilgol N.
- Religion briefs for Sept. 19 | Community - Petoskey News-Review - September 19th, 2019
- Joseph M. Sanzari Childrens Hospital and John Theurer Cancer Center Launch Clinical Trial Evaluating Gene Therapy for Severe Sickle Cell Disease in... - September 19th, 2019
- Engineering lymphatic vessels as a therapeutic to heal the heart - ND Newswire - September 19th, 2019
- SanBio Granted Regenerative Medicine Advanced Therapy Designation from the US FDA for SB623 for the Treatment of Chronic Neurological Motor Deficits... - September 19th, 2019
- Stem Cell Therapies Market by Top Key Players, Size, Subdivision & Market Dynamics Forces - NewsVarsity - September 19th, 2019
- Stem Cell Assay Market to Record an Exponential CAGR by 2025 - Wolf Mirror - September 19th, 2019
- Mesenchymal Stem Cells Market to Witness Heightened Revenue Growth in the Next Decade - NewsVarsity - September 19th, 2019
- Knotty Problem of Cell Reprogramming Solved - Technology Networks - September 19th, 2019
- Stem Cell Therapy Market Foraying into Emerging Economies 2017-2025 - Techdadz - September 19th, 2019
- Canine Stem Cell Therapy Market is expected to witness a CAGR of 4.2% during the forecast period 2017-2026 - Zebvo - September 19th, 2019
- Alzheimer's Disease Insight Report: Current Therapies, Drug Pipeline and Outlook - BioSpace - September 19th, 2019
- Partner Therapeutics Receives Orphan Drug Designation for Leukine (sargramostim) - Odessa American - September 19th, 2019
- Stem Cells Market Predicted to Surpass US$167.33 Bn By 2025 - TheSlapClap - September 19th, 2019
- Story of life: Seven wonders of biological research - The Irish Times - September 19th, 2019
- Cell Harvester Market Share, Growth by Top Company, Region, Applications, Drivers, Trends & Forecast to 2025 - Market Forecast - September 19th, 2019
- Tracing the origin of adult intestinal stem cells | Nature - May 20th, 2019
- StemEnhance Ultra: The Best Stem Cell Supplement - May 12th, 2019
- Adult Stem Cell Therapy - regenocyte.com - April 28th, 2019
- Summary: What is an Adult Stem Cell? | Stem Cells Portal ... - April 28th, 2019
- Adult Stem Cell Therapy Is A Resounding Healing Success, So ... - March 21st, 2019
- FDA Wants to Shut Down Adult Stem Cell Therapy as its Healing ... - March 21st, 2019
- Past Years of Hype Notwithstanding, Adult Stem Cells Are Now ... - March 21st, 2019
- Stem Cells & David A. Prentice -- Adult Stem Cells Are Now ... - March 18th, 2019
- Adult stem cell therapies are coming to market - Jun. 16, 2009 - March 17th, 2019
- Adult Cardiac Stem Cells Don't Exist: Study | The Scientist ... - March 17th, 2019
- Adult Stem Cell Therapy for Osteoarthritis & Joint Injuries ... - March 17th, 2019
- David Lindsay: Adult Stem Cells Are Now The Gold Standard - March 17th, 2019
- A few questions about stem cells? | Yahoo Answers - February 22nd, 2019
- What are adult stem cells? - StemExpress Donor Center - February 1st, 2019
- Adult Stem Cells // Center for Stem Cells and Regenerative ... - February 1st, 2019
- What is Adult Stem Cell Therapy? | Okyanos Center for ... - January 19th, 2019
- Conditions and Diseases Treated | Adult Stem Cell Therapy - December 12th, 2018
- 6 Pros and Cons of Adult Stem Cells | Green Garage - December 2nd, 2018
- Adult Stem Cells Show Anti-Aging Potential - genengnews.com - November 28th, 2018
- Induced pluripotent stem cell - Wikipedia - November 8th, 2018
- What Are The Similarities And Differences Between Embryonic ... - September 30th, 2018
- stem cell | Definition, Types, Uses, Research, & Facts ... - September 16th, 2018
- Fact Sheet: Adult Stem Cell Research and Transplants ... - September 16th, 2018
- Stem Cell Therapy and Stem Cell Injection Provider Finder ... - August 19th, 2018
- Understanding Adult and Embryonic Stem Cell Research - August 13th, 2018
- Types of Adult Stem Cells Stem Cell Institute StemCell ... - July 29th, 2018
- Difference between Adult and Embryonic Stem Cells - July 29th, 2018
- Stem Cells, Characteristics, Properties, Different ... - July 29th, 2018
- Adult Stem Cell Research Leaving Embryos Behind - CBS News - July 24th, 2018
- 5 Benefits to Using Adult Stem Cells in Cancer Research - July 5th, 2018
- Sources of Adult Stem Cells - Stem Cell Institute - July 5th, 2018
- Adult Stem Cell Therapy 101, MSCTC - July 5th, 2018
- What are Adult Stem Cells? | Adult Stem Cell Treatment - July 2nd, 2018
- Your Stem Cell Questions Answered - webmd.com - October 13th, 2017
- Adult Stem Cell Therapy in Cancer, MSCTC - KUMC - October 13th, 2017
- Adult Stem Cells in Greenville, SC - September 23rd, 2017
- How Adult Stem Cells Can Help Stop Pain and Reverse Aging - September 23rd, 2017
- 4. The Adult Stem Cell | stemcells.nih.gov - September 19th, 2017
- Researchers point way to improved stem cell transplantation therapies - Medical Xpress - September 8th, 2017
- Clarkson professor awarded $420000 grant to study development of intestinal stem cells using zebrafish vertebrate ... - North Country Now - September 8th, 2017
- FDA Grants Orphan Drug Status to Cellect's ApoGraft for Acute GvHD and Chronic GvHD - Markets Insider - September 6th, 2017
- Presto Therapeutics Recruits Top Names For Advisory Boards - Business Wire (press release) - September 6th, 2017
- Stem Cell Market Analysis 2022: Latest Trends, Top Manufactures and Business Opportunities - satPRnews (press release) - September 3rd, 2017
- Ethical Stem Cells Relieve Parkinson's in Monkeys - National Review - September 1st, 2017
- Are stems cells really the fountain of youth? - Star2.com - Star2.com - September 1st, 2017
- ORGANOID - Science Magazine - August 23rd, 2017
- The Adult Brain Can Regenerate Neurons in an Unexpected Area, Says New Study - ScienceAlert - August 22nd, 2017
- ASC Biosciences, Inc. to appear on the "Informed" series hosted by Rob Lowe - Markets Insider - August 22nd, 2017
- Want to live longer? Forever Labs wants to help, using your stem cells - Digital Trends - August 22nd, 2017
- Adult brain's fear HQ can grow new cells - Cosmos - August 16th, 2017
- Adult brains produce new cells in previously undiscovered area - Medical Xpress - August 16th, 2017
- Orphan Black is ending, but how far has human cloning come? - The Verge - August 13th, 2017
- Is stem cell injection the cure-all miracle? - Health24 - August 10th, 2017
- Advancells Announces Successful Reversal of Multiple Sclerosis Through Adult Stem Cell Therapy - New Kerala - August 4th, 2017
- Gene editing used to repair diseased genes in embryos - NHS Choices - August 3rd, 2017
- Stem Cells Offer New Solutions for Lung Disease - Miami's Community Newspapers - August 1st, 2017
- Hypothalamic Stem Cells Control Aging in Mice - Sci-News.com - July 31st, 2017
- Stem cells in brain located by scientists could help reverse ageing process - The Independent - July 30th, 2017
- Only as Old as the Brain's Stem Cells Feel - Genetic Engineering & Biotechnology News - July 30th, 2017
- Regenerative Medicine: The Future of Medicine is Here Miami's ... - Miami's Community Newspapers - July 13th, 2017
- Unanimous Advice To FDA: Approve Landmark CAR-T Cancer Therapy - Xconomy - July 13th, 2017
- Adult Stem Cells Save Woman Ravaged by Lupus, Now She Can be a Mom - LifeNews.com - July 3rd, 2017
- Scientists Turn Back the Clock on Adult Stem Cells Aging ... - July 3rd, 2017
- A*STAR scientists identify role of key stem cell factor in gastric cancer progression - Biotechin.Asia - July 3rd, 2017
- Adult Stem Cell Banking Information from Celltex Therapeutics - January 27th, 2017