New Avenues for Brain Repair
by Paola Arlotta, Benedikt Berninger, Alejandro Schinder and Abcam
1 Reprogramming of somatic cells into neurons and glia via a pluripotent intermediate stage [1-6]

2 Direct lineage reprogramming of somatic cells into neurons [8-15]
Astrocyte

FGF8,Retinoic acid,Shh, EGF, FGF2

VGAT, GAD65/67

(ALS)

Mouse

Ascl1, Dlx2

Astrocytes

Foxg1

Cortical neuron(Stroke, Alzheimer’s,Schizophrenia, Fragile X)

Mouse or human
Fibroblasts

Oct4, Sox2,Klf4, c-myc

iPSCs

Tyrosine hyroxylase
Dopamine neuron(Parkinson’s)

FGF8b, Shh

Retinoic acid, Shh

Hb9, Islet1, ChATGABAergic interneuron(Stroke, Alzheimer’s, Epilepsy)

VGlut1, CamKll alpha

Neurog2
Ascl1, Brn2,Myt1l, NeuroD1

Healthyhuman

Parkinson’s
diseasesuﬀerer

Cortical neuron(Stroke, Alzheimer’s)

Ascl1, Brn2, Myt1l,
Lmx1a, FoxA2

Tyrosine hyroxylase
Dopamine neuron(Parkinson’s)

Fibroblasts
Ascl1, Brn2, Myt1l, Lhx3, Hb9,
Islet 1, Neurog2

ChAT, VAChT, HB9, Islet 1
Spinal motor neurons

Spinal motor neuron(ALS, spinal cord injury)

Fibroblasts or other somatic cells can be reprogrammed into induced pluripotent stem cells (iPSCs) by a defined cocktail of transcription factors. These iPSCs are very similar to embryonic stem cells
and can be selectively driven towards the genesis of neurons and glia, either by signaling molecules or by specific transcription factors. Many clinically important types of neurons have been generated
in vitro using this strategy, also from patients suffering from neurodegenerative diseases like Parkinson’s disease. Patient iPSC-derived neurons can be used to study the mechanisms underlying thedisease’s pathology.

3 Lineage reprogramming in vivo [16]Instead of reprogramming via a pluripotent intermediate, somatic cells can also be reprogrammed directly. Mouse astroglia can be reprogrammed into glutamatergic and GABAergic neurons by forced
expression of Neurog2 or Ascl1, respectively. Alternatively, fibroblasts can be directly converted into various types of neurons, including glutamatergic, dopaminergic and spinal motor neurons, bydifferent cocktails of transcription factors and neuron-specific microRNAs. Neurons derived from fibroblasts of a patient with Alzheimer’s disease have revealed defects in the processing and localizationof amyloid precursor protein.

4 Learning from adult neurogenesis the rules for integration into a neuronal network [17-21]

PAX6

GSX2

GCL
GABAergic
Interneurons

Mash1
CA3 Pyramidal Neurons
Apical dendrites

Neurog2+ forced
expression of fezf2

Mediumspiny neuron

GABAergic medium spiny neuron progenitors can be lineage reprogrammed into corticofugal neurons, solely by forced expression of the transcription factor Fezf2. Amazingly, some axons of thesecorticofugal neurons direct themselves to the spinal cord, very similar to those of corticospinal motor neurons. Corticospinal motor neurons are a neuron population that dies in amyotrophic lateralsclerosis (ALS) but also become severed in spinal cord injury. A future challenge is to examine the possibility of such lineage reprogramming in the adult CNS in order to replace neurons degenerated
due to disease or injury.

4 daysGABAARα2-5
DISC1

1 weekNKCC1

2 weekDISC1

3-4 week DISC1
Basal dendrites

Pyramidal
neuronPerforant PathNR2B

DARPP32+
GABAergic

Fezf2+
Glutamatergic

2 daysAxon

GABAARα1Kir
NR2A
KCC2>6 weeks MATURE

A key challenge of all approaches to cell-based therapy concerns the integration of new neurons into a pre-existing neuronal network. The adult neurogenesis process taking place in the dentate gyrusof the hippocampus (depicted) and the adult olfactorybulb provides examples of how this can occur. The survival and maturation of newly generated neurons depends on receiving signals from thesurrounding network, e.g. GABA and neurotrophins. Additionally, maturation of new neurons is a protracted process, normally slowed down by DISC1, a gene implicated in schizophrenia.

References:

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N.B. The above reading list is not exhaustive and is only intended to provide a quick overview of the topic.

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