Regeneration, Repair, and Plasticity (continued) Chapters 6, 7, 8, 10 P.S. Timiras

Anatomical Correlates of Educational Protective Effects* Educational Level Increasing levels from 12 grades Anatomical Correlate total dendritic length mean dendritic length dendritic segment count Location Pyramidal cells in layer 2,3 of Wernicke’s area Variable Studied Gender Hemisphere Education Personal history Hormonal Correlate Thyroid Hormones dendritic number and length Glucocorticoids reactive synaptogenesis ______________ * From Jacobs et al., J Comp. Nuerol., 327, 97, 1993

Evidence from several laboratories show: That in the brain there are neural cells which can divide These are cells located in: olfactory bulbs hippocampus ependymal cells (in proximity of the ventricles) glial cells (astrocytes which can de-differentiate & differentiate into neurons) From Wong, R.J., Thung, E., et al., Keeping Cells Young: The role of growth factors in restricting cell differentiation in cultured neuroglia, FASEB Journal, 17(5): A967, 2003.

Common ectodermic derivation of neurons and neuroglia Astrocytes: Star shaped cells Support neurons metabolically Assist in neuronal transmission Oligodendrocytes: myelinate neurons Neural Epithelium NeuroblastSpongioblast NeuronMigratory Spongioblast Astrocyte Ependyma Oligodendrocyte Astrocyte Neural Cells

Growth Curves Measuring Neuroglial Cell Proliferation EGF FGF * Proliferation increased most effectively with the 50 ng/ml dose (193% over control cells) for EGF, reaching a peak at day 10 * Proliferation increased most effectively with the 80 ng/ml dose (269% over control cells) for FGF, reaching a peak at day 8

Assays of enzymatic activity (e.g. glutamine synthetase--a marker of astrocytes) show decreased activity suggesting a loss of astrocytic specificity From: Proliferation Maturation To: Proliferation De-differentiation

Astrocyte “Activated” astrocyte Proliferating astrocytes Neuroblast migrate From: Doetsch, F., et al., Neuron, 36:1021, 2002.

Blue: DAPI (stains nucleus) Red: NeuN (a neuronal marker) Untreated gliaEGF treated glia FGF treated glia Control: Neurons

Tsonis, P.A., Stem Cells from Differentiated Cells, Mol. Interven.,4, 81-83, 2004 From newt amputated limb, terminally differentiated cells de-differentiate by losing their original characteristics. This de-differentiation produces blastema cells that then re- differentiate to reconstitute the lost limb. After lentectomy de- differentiated cells lose pigment and regenerate a perfect lens. De-differentiated myotubes produce mesenchymal progenitor cells that are able to differentiate in adipocytes and osteoblasts. Also refer to: Brawley, C. and Matunis, E., Regeneration of male germ line stem cells by spermatogonial de-differentiation in vivo. Science 304,

Muscle cells Muscle cells, like neurons, –do not usually divide –do not regenerate after trauma/damage/old age. This is interpreted as a decline in regeneration/specific signaling. Special cells -- satellite cells -- act as myocyte’s progenitor cells. –When exposed to a young systemic milieu, these cells upregulate specific genes and successfully regenerate/repair the damaged old tissue. Muscle cells, like neurons, –do not usually divide –do not regenerate after trauma/damage/old age. This is interpreted as a decline in regeneration/specific signaling. Special cells -- satellite cells -- act as myocyte’s progenitor cells. –When exposed to a young systemic milieu, these cells upregulate specific genes and successfully regenerate/repair the damaged old tissue.

Get Up and Move: A Call to Action for Older Men & Women The brain regulates motor function and, reciprocally, Motor function influences brain activity Throughout life, One’s behavior can change the structure of the brain And these changes Can affect how we behave in our environment

Additional Studies To promote regeneration/repair responses in aging muscle: –Injection of growth hormone in aging cardiac muscle –Implantation of stem cells into infarcted cardiac muscle To promote regeneration/repair responses in aging muscle: –Injection of growth hormone in aging cardiac muscle –Implantation of stem cells into infarcted cardiac muscle