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Multipotent progenitor cells from the adult human brain: neurophysiological differentiation to mature neurons

Moe, Morten C ; Varghese, Mercy ; Danilov, Alexandre LU ; Westerlund, Ulf ; Ramm-Pettersen, Jon ; Brundin, Lou ; Svensson, Mikael ; Berg-Johnsen, Jon and Langmoen, Iver A (2005) In Brain 128(9). p.2189-2199
Abstract
It was long held as an axiom that new neurons are not produced in the adult human brain. More recent studies have identified multipotent cells whose progeny express glial or neuronal markers. This discovery may lead to new therapeutic strategies for CNS disorders, either by stimulating neurogenesis in vivo or by transplanting multipotent progenitor cells (MPCs) that have been propagated and differentiated in vitro. The clinical application of such approaches will be limited by the ability of these cells to develop into functional neurons. To facilitate an understanding of mechanisms regulating neurogenesis in the adult human brain, we characterized the developmental processes MPCs go through when progressing to a neuron. Human tissue was... (More)
It was long held as an axiom that new neurons are not produced in the adult human brain. More recent studies have identified multipotent cells whose progeny express glial or neuronal markers. This discovery may lead to new therapeutic strategies for CNS disorders, either by stimulating neurogenesis in vivo or by transplanting multipotent progenitor cells (MPCs) that have been propagated and differentiated in vitro. The clinical application of such approaches will be limited by the ability of these cells to develop into functional neurons. To facilitate an understanding of mechanisms regulating neurogenesis in the adult human brain, we characterized the developmental processes MPCs go through when progressing to a neuron. Human tissue was harvested during temporal lobe resections because of epilepsy, and cells were cultured as neurospheres. Our findings demonstrate that at an early stage, these cells often stain with neuronal markers without possessing any functional neuronal properties. Over a period of 4 weeks in culture, cells go through characteristic steps of morphological and electrophysiological development towards functional neurons; they develop a polarized appearance with multiple dendrites, whereas the membrane potential becomes more negative and the input resistance decreases [from -48 +/- 10 mV/557 +/- 85 MOmega (n = 15) between days 7 and 11 to -59 +/- 9 mV/380 +/- 79 MOmega (n = 9) between days 25 and 38, respectively]. Active membrane properties were first observed on day 7 and consisted of a voltage-gated K+-current. Later in the second week the cells developed voltage-gated Ca2+-channels and fired small Ca2+-driven action potentials. Immature Na+-driven action potentials developed from the beginning of the third week, and by the end of the fourth week the cells fired repetitive action potentials with a completely mature waveform generated by the combined action of the voltage-gated ionic channels INa, IA and IK. After 4 weeks, the newly formed neurons also communicated by the use of GABAergic and glutamatergic synapses. The adult human brain thus harbours MPCs, which have the ability to develop into neurons and in doing this follow characteristic steps of neurogenesis as seen in the developing brain. (Less)
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author
; ; ; ; ; ; ; and
publishing date
type
Contribution to journal
publication status
published
subject
keywords
multipotent precursors, human brain stem cells, action potentials, differentiation, synaptic connections
in
Brain
volume
128
issue
9
pages
2189 - 2199
publisher
Oxford University Press
external identifiers
  • pmid:15958504
  • scopus:24344432394
ISSN
1460-2156
DOI
10.1093/brain/awh574
language
English
LU publication?
no
id
29fd693f-f728-403d-9fb4-1f8a664639d9 (old id 1134278)
date added to LUP
2016-04-01 12:31:18
date last changed
2024-01-08 23:21:12
@article{29fd693f-f728-403d-9fb4-1f8a664639d9,
  abstract     = {{It was long held as an axiom that new neurons are not produced in the adult human brain. More recent studies have identified multipotent cells whose progeny express glial or neuronal markers. This discovery may lead to new therapeutic strategies for CNS disorders, either by stimulating neurogenesis in vivo or by transplanting multipotent progenitor cells (MPCs) that have been propagated and differentiated in vitro. The clinical application of such approaches will be limited by the ability of these cells to develop into functional neurons. To facilitate an understanding of mechanisms regulating neurogenesis in the adult human brain, we characterized the developmental processes MPCs go through when progressing to a neuron. Human tissue was harvested during temporal lobe resections because of epilepsy, and cells were cultured as neurospheres. Our findings demonstrate that at an early stage, these cells often stain with neuronal markers without possessing any functional neuronal properties. Over a period of 4 weeks in culture, cells go through characteristic steps of morphological and electrophysiological development towards functional neurons; they develop a polarized appearance with multiple dendrites, whereas the membrane potential becomes more negative and the input resistance decreases [from -48 +/- 10 mV/557 +/- 85 MOmega (n = 15) between days 7 and 11 to -59 +/- 9 mV/380 +/- 79 MOmega (n = 9) between days 25 and 38, respectively]. Active membrane properties were first observed on day 7 and consisted of a voltage-gated K+-current. Later in the second week the cells developed voltage-gated Ca2+-channels and fired small Ca2+-driven action potentials. Immature Na+-driven action potentials developed from the beginning of the third week, and by the end of the fourth week the cells fired repetitive action potentials with a completely mature waveform generated by the combined action of the voltage-gated ionic channels INa, IA and IK. After 4 weeks, the newly formed neurons also communicated by the use of GABAergic and glutamatergic synapses. The adult human brain thus harbours MPCs, which have the ability to develop into neurons and in doing this follow characteristic steps of neurogenesis as seen in the developing brain.}},
  author       = {{Moe, Morten C and Varghese, Mercy and Danilov, Alexandre and Westerlund, Ulf and Ramm-Pettersen, Jon and Brundin, Lou and Svensson, Mikael and Berg-Johnsen, Jon and Langmoen, Iver A}},
  issn         = {{1460-2156}},
  keywords     = {{multipotent precursors; human brain stem cells; action potentials; differentiation; synaptic connections}},
  language     = {{eng}},
  number       = {{9}},
  pages        = {{2189--2199}},
  publisher    = {{Oxford University Press}},
  series       = {{Brain}},
  title        = {{Multipotent progenitor cells from the adult human brain: neurophysiological differentiation to mature neurons}},
  url          = {{http://dx.doi.org/10.1093/brain/awh574}},
  doi          = {{10.1093/brain/awh574}},
  volume       = {{128}},
  year         = {{2005}},
}