Brain Advance Access originally published online on June 15, 2005
Brain 2005 128(9):2189-2199; doi:10.1093/brain/awh574
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Multipotent progenitor cells from the adult human brain: neurophysiological differentiation to mature neurons
1 Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden, 2 Institute for Surgical Research and Department of Neurosurgery, Rikshospitalet, University of Oslo, Norway and 3 Neuroimmunology Unit, Centre of Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
Correspondence to: Morten C. Moe, MD, PhD, Department of Clinical Neuroscience, Karolinska Institutet, 171 76 Stockholm, Sweden E-mail: Morten.Moe{at}cns.ki.se
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 M
(n = 15) between days 7 and 11 to –59 ± 9 mV/380 ± 79 M (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.
Key Words: action potentials; differentiation; human brain stem cells; multipotent precursors; synaptic connections
Abbreviations: 4-AP = 4-aminopyridine; [Ca2+]i = intracellular Ca2+; CNQX = 6-cyano-7-nitroquinoxaline-2,3-dione; FCS = fetal calf serum; L15 = Leibowitz-15 medium; MK-801 = D-2-amino-5-phosphonovaleric acid; MPCs = multipotent progenitor cells; NiCl = nickel chloride; SCs = stem cells; TEA = tetraethylammonium; TCSM = Time Course/Ratiometric Software Module; TTX = tetrodotoxin; VGlut-1 = glutamate transporter-1; VZ = ventricular zone
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Received November 17, 2004. Revised May 10, 2005. Accepted May 20, 2005.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors
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