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Good health while aging depends upon optimal cellular and organ functioning that contribute to the regenerative ability of the body during the lifespan, especially when injuries and diseases occur. Although diet may help in the maintenance of cellular fitness during periods of stability or modest decline in the regenerative function of an organ, this approach is inadequate in an aged system, in which the ability to maintain homeostasis is further challenged by aging and the ensuing suboptimal functioning of the regenerative unit, tissue-specific stem cells. Focused nutritional approaches can be used as an intervention to reduce decline in the body's regenerative capacity. This article brings together nutrition-associated therapeutic approaches with the fields of aging, immunology, neurodegenerative disease, and cancer to propose ways in which diet and nutrition can work with standard-of-care and integrated medicine to help improve the brain's function as it ages. The field of regenerative medicine has exploded during the past 2 decades as a result of the discovery of stem cells in nearly every organ system of the body, including the brain, where neural stem cells persist in discrete areas throughout life. This fact, and the uncovering of the genetic basis of plasticity in somatic cells and cancer stem cells, open a door to a world where maintenance and regeneration of organ systems maintain health and extend life expectancy beyond its present limits. An area that has received little attention in regenerative medicine is the influence on regulatory mechanisms and therapeutic potential of nutrition. We propose that a strong relation exists between brain regenerative medicine and nutrition and that nutritional intervention at key times of life could be used to not only maintain optimal functioning of regenerative units as humans age but also play a primary role in therapeutic treatments to combat injury and diseases (in particular, those that occur in the latter one-third of the lifespan)., Competing Interests: Author disclosures: The authors are affiliated with a new start-up company, Prana Therapeutics, Inc. They have received no financial compensation in relation to this article., (© 2017 American Society for Nutrition.)

Identifying novel, effective therapeutics for Alzheimer's disease (AD) is one of the major unmet medical needs for the coming decade. Because the current paradigm for developing and testing disease-modifying AD therapies is protracted and likely to be even longer, with the shift toward earlier intervention in preclinical AD, it is an open issue whether we can develop, test, and widely deploy a novel therapy in time to help the current at-risk generation if we continue to follow the standard paradigms of discovery and drug development. There is an imperative need to find safe and effective preventive measures that can be distributed rapidly to stem the coming wave of AD that will potentially engulf the next generation. We can define regenerative medicine broadly as approaches that use stem cell-based therapies or approaches that seek to modulate inherent neurogenesis. Neurogenesis, although most active during prenatal development, has been shown to continue in several small parts of the brain, including the hippocampus and the subventricular zone, suggesting its potential to reverse cognitive deficits. If AD pathology affects neurogenesis, then it follows that conditions that stimulate endogenous neurogenesis (eg, environmental stimuli, physical activity, trophic factors, cytokines, and drugs) may help to promote the regenerative and recovery process. Herein, we review the complex logistics of potentially implementing neurogenesis-based therapeutic strategies for the treatment of AD., (Copyright © 2014 Mosby, Inc. All rights reserved.)

Bone sarcomas are a clinically and molecularly heterogeneous group of malignancies characterized by varying degrees of mesenchymal differentiation. Despite advances in medical and surgical management, survival rates for high-grade tumors have remained static at 50% to 70%. Tumor stem cells have been recently implicated in the pathogenesis of other heterogeneous, highly malignant tumors. We demonstrate here the existence of a small subpopulation of self-renewing bone sarcoma cells that are capable of forming suspended spherical, clonal colonies, also called "sarcospheres," in anchorage-independent, serum-starved conditions. These bone sarcoma cells as well as tissue specimens express activated STAT3 and the marker genes of pluripotent embryonic stem (ES) cells, Oct 3/4 and Nanog. Expression levels of Oct 3/4 and Nanog are greater in sarcospheres than in adherent cultures. A subset of bone sarcoma cells displays several surface markers of mesenchymal stem cells (Stro-1, CD105, and CD44) as well as attributes of mesodermal, ectodermal, and endodermal differentiation. Although previously documented in brain and breast tumors, our results support the extension of the cancer stem cell hypothesis to include tumors of mesenchymal lineage. Furthermore, they suggest the participation of ES cell homeobox proteins in non-germ cell tumorigenesis.

Background: End-organ repair by adult haemopoietic stem cells is under great scrutiny with investigators challenging the notion of these cells' plasticity. Some investigations of animals and short-term human bone marrow transplants suggest that bone marrow can repair brain. We looked for evidence of clinically relevant marrow-derived restorative neurogenesis: long-term, multilineage, neural engraftment that is not the result of cell-fusion events., Methods: We examined autopsy brain specimens from three sex-mismatched female bone-marrow-transplantation patients, a female control, and a male control. We did immunohistochemistry, fluorescence in-situ hybridisation, and tissue analysis to look for multilineage, donor-derived neurogenesis., Findings: Hippocampal cells containing a Y chromosome were present up to 6 years post-transplant in all three patients. Transgender neurons accounted for 1% of all neurons; there was no evidence of fusion events since only one X chromosome was present. Moreover, transgender astrocytes and microglia made up 1-2% of all glial cells., Interpretation: Postnatal human neuropoiesis happens, and human haemopoietic cells can transdifferentiate into neurons, astrocytes, and microglia in a long-term setting without fusing. Transplantable human haemopoietic cells could serve as a therapeutic source for long-term regenerative neuropoiesis.

Stem cells in adult tissues have attracted a great deal of interest. These cells are self-renewing and can give rise to diverse progeny. An extraordinary finding was the presence of stem cells in the mature human brain. This tissue was previously believed incapable of generating new neurons, but neuropoiesis is now an established phenomenon in the adult brains of mammals, including human beings. This persistent neurogenesis has potential therapeutic applications for various neurological disorders as a source for tissue engraftment and as self-repair by a person's own indigenous population of pluripotent cells or biogenic by-products of their proliferation and differentiation.

From all of the studies of developmentally regulated molecules as well as the impressive proliferation of cells within the SEZ, we would like to propose that the SEZ of the adult brain, from the lateral ventricles of the cerebrum to the central canal of the spinal cord, represents a potential "brain marrow" from which stem and progenitor cells can be further studied and exploited for cell replacement and circuitry repair paradigms for neurological disease. Without question the SEZ is not as regenerative or pleuripotential as bone marrow or other hematopoietic systems, but there are definitely some elements in common. Bone marrow contains a pleuripotent stem cell that under certain conditions (e.g. the presence of certain growth factors and cytokines) gives rise to erythroblasts and myeloblasts whose progeny include erythrocytes, monocytes, thrombocytes and macrophages. Different growth factors can likewise affect the proliferation as well as differentiation of adult CNS stem and progenitor cells, again contributing to diverse cellular phenotypes. The roles for matrix molecules in these events are yet to be discovered, however, there is evidence to suggest that matrix molecules, including tenascin, do interact with hematopoietic stem cells (Yoder and Williams, 1995) to possibly affect their proliferation and differentiation. Future studies might reveal a similar role for the dense ECM expression within the SEZ proliferative/migratory pathway.

Certain types of glial structures, located at strategic positions along axon pathways, may provide the mechanical and/or chemical elements for the construction of barriers which can grossly direct the elongation of axons during development. The roof plate, a putative axon barrier, is located along the dorsal midline of the developing spinal cord and may be important for the guidance of the commissural and dorsal column axons. We examined the roof plate to determine the developmental morphology of the region and to determine which molecules were correlated with the barrier function when axons were growing nearby. Light and electron microscopic observations of the roof plate revealed that this glial domain undergoes a dramatic change in shape from a "wedge" with large extracellular spaces between the cell apices at E12.5 to a thin, dense septum with reduced extracellular space at E15.5. Immunocytochemical techniques demonstrated that highly sialylated neural cell adhesion molecule (N-CAM), the carbohydrate recognized by L2 monoclonal antibody, cholinesterase, stage-specific embryonic antigen 1, and a ligand that binds tetragonolobus purpureas agglutinin are expressed by the roof plate. These molecules, however, were also found in other regions of the spinal cord which are permissive or attractive to axon growth. A molecule which is unique to the roof plate when axons grow close to, but do not cross, the dorsal midline is a glycosaminoglycan (GAG), keratan sulfate. Keratan sulfate is also present in the tectal midline and in other noninnervated regions such as the outer epidermis and developing cartilage. Our data suggest that keratan sulfate, alone or in combination with other molecules expressed by the roof plate, may be responsible, in part, for the inhibition of axon elongation through the roof plate in the embryonic spinal cord.

The distribution of the 200/220 KDa J1 glycoprotein (J1-200/220), within the developing vibrissae-related barrel field of the mouse somatosensory cortex, was studied by immunocytochemistry using a monoclonal antibody. J1-200/220, a member of the L2/HNK-1 family of adhesion molecules, also appears to be the mouse homologue of tenascin. J1/tenascin-positive barrel-like structures are visible in the somatosensory cortex between 24 and 48 hr after birth, with the molecule present in prospective barrel boundaries. Immunoelectronmicroscopy reveals labeling that is associated with glial and neuronal plasma membranes, as well as glial end-feet on blood vessels. A possible major source of J1/tenascin expression at this time is astrocyte precursor cells and radial glia. In the putative astrocyte precursor cells, immunolabeling was observed within organelles including the Golgi apparatus. At P6-7 J1/tenascin is most prevalent within prospective interbarrel septae. J1/tenascin-positive barrel boundaries are barely visible on P9 and not observed on P16. The findings indicate that J1/tenascin represents a major component of previously described "hidden" boundaries that we have seen during development using other methodologies. The expression of adhesion molecule-rich boundaries during the critical stages of barrel field formation indicates roles for such molecules during specific cerebral cortical pattern formation events.

The morphology of dorsal raphe neurons was examined using intracellular injections of horseradish peroxidase (HRP) and the Golgi technique. Light microscopic examination of HRP-labeled projection neurons revealed a neuron type with radiating, poorly branched and sparsely spined dendrites and terminal dendritic thickets. The stem axon of these neurons left the nucleus ventrally but gave off a beaded collateral while still within the parent cell's dendritic domain. Somatodendritic morphology from Golgi-Kopsch stained material coincided with intracellular HRP findings and the dorsal raphe may consist of varieties of one basic morphological type of neuron. Intracellular recordings made during the HRP injection experiments confirmed that stimulation of the ventral medial tegmentum elicited an antidromic action potential and an inhibitory postsynaptic potential in dorsal raphe projection neurons. The order of axonal projections arising from the midbrain raphe nuclei was examined using a double retrograde axonal tracing technique. After paired HRP and [3H] wheat germ agglutinin injections within certain projection targets of the dorsal and median raphe neurons (caudate-putamen, amygdala, hippocampus, substantia nigra and locus coeruleus), each target structure was found to have its own unique representation within a topographically distinct portion of one or more of the raphe subgroups. Neurons projecting to the caudate-putamen and substantia nigra occupied rather rostral portions. Neurons projecting to the hippocampus and locus coeruleus resided more caudally. Neurons projecting to the amygdala were situated intermediately. Overall, rostrocaudal topography in the intranuclear distributions of raphe projection neurons resulted in the formation of complex overlap zones where collateralized neurons always resided.