Regeneration, Repair, and Plasticity (continued)

Regeneration, Repair, and Plasticity (continued)

Chapters 6, 7, 8, 10P.S. Timiras

Anatomical Correlates of Educational Protective Effects*Educational Level Increasing levels from <12 to >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 GenderHemisphereEducationPersonal history

Hormonal Correlate Thyroid Hormones dendritic number and length Glucocorticoids reactive synaptogenesis ______________* From Jacobs et al., J Comp. Nuerol., 327, 97, 1993

RISK FACTORS FORDEMENTIA

Age

Family history

Head injury

Fewer years of education

Evidence from several laboratories show: That in the brain there are neural cells which can

divideThese are cells located in:

olfactory bulbshippocampus

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 cellsSupport neurons metabolicallyAssist in neuronal transmission

Oligodendrocytes: myelinate neurons

Neural Epithelium

Neuroblast Spongioblast

Neuron Migratory Spongioblast Astrocyte Ependyma

Oligodendrocyte Astrocyte

Neural Cells

Growth Curves Measuring Neuroglial Cell Proliferation

Effects of FGF on Neuroglial Cells

0

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Length of Trial in Days

Num

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Control

FGF - 40

FGF - 80

FGF - 160

Effects of EGF on Neuroglial Cells

0

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200000

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Length of Trial in Days

Num

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25 ng/ml

50 ng/ml

100 ng/ml

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”

astrocyteProliferating

astrocytes Neuroblast

migrate

From: Doetsch, F., et al., Neuron, 36:1021, 2002.

Blue: DAPI (stains nucleus)Red: NeuN (a neuronal marker)

Untreated glia EGF 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, 1331-1334. 2004

Muscle cellsMuscle 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.

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 changesCan affect how we behave in our environment

Additional StudiesAdditional 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