Functional Properties of Motoneurons Derived from Mouse Embryonic Stem Cells

Miles, Gareth B.; Yohn, Damien C.; Wichterle, Hynek; Jessell, Thomas M.; Rafuse, Victor F.; Brownstone, Robert M.

doi:10.1523/jneurosci.1972-04.2004

Cited by 192 publications

(207 citation statements)

References 61 publications

(82 reference statements)

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“…Our own studies on embryonic stem cell-derived motoneurons found that these neurons in many ways resembled motoneurons (Miles et al, 2004;Soundararajan et al, 2006). These cells demonstrated early SFA, yet were found not to have a measurable AHP conductance (Miles et al, 2004).…”

Section: Spike Frequency Adaptationmentioning

confidence: 94%

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Beginning at the end: Repetitive firing properties in the final common pathway

Brownstone

2006

Progress in Neurobiology

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Since the early 20th century, it has been recognized that motoneurons must fire repetitive trains of action potentials to produce muscle contraction. In 1932, Sir John Eccles, together with Hebbel Hoff, found that action potential spike trains in motor axons were produced by "rhythmic centres", which were within the motoneurons themselves. Two decades later, Eccles attended a Cold Spring Harbor Symposium in NY, USA entitled "The Neuron". Two of the many notable presentations at this symposium were juxtaposed: one by Eccles from the University of Otago, Dunedin, NZL, and the other by J. Walter Woodbury and Harry Patton from the University of Washington, Seattle, USA. Both presentations included data obtained using sharp microelectrodes to study the intracellularly recorded potentials of cat motoneurons. In this review, I discuss some of the events leading up to and surrounding this jointly accomplished advance and proceed to discussion of subsequent studies over 5+ decades that have made use of intracellular recordings from motoneurons to study their repetitive firing behavior. This begins with early descriptions of primary and secondary range firing, and continues to the discovery of dendritic persistent inward currents and their relation to plateau potentials, synaptic amplification, and motoneuronal firing. Following a brief description of the possible mechanisms underlying spike frequency adaptation, I discuss the modulation of repetitive firing properties during various motor behaviors. It has become increasingly clear that the central nervous system has exquisite control of the repetitive firing of motoneurons. Eccles' work laid the foundation for the present-day study of these processes.

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Section: Spike Frequency Adaptationmentioning

confidence: 94%

“…These cells demonstrated early SFA, yet were found not to have a measurable AHP conductance (Miles et al, 2004). This prompted us to study SFA in endogenous mouse motoneurons in spinal slices.…”

Section: Spike Frequency Adaptationmentioning

confidence: 99%

Beginning at the end: Repetitive firing properties in the final common pathway

Brownstone

2006

Progress in Neurobiology

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“…The application of both RA and Shh during embryoid body formation in murine ESCs was investigated by Wichterle et al [22], Miles et al [23], Kothapalli and Kamm [24], Brown et al [25], and in human ESCs by Li et al [26], Stacpoole et al [27], and Hu and Zhang [28], among others. Such studies have revealed the synergistic effects of these two factors.…”

Section: Introductionmentioning

confidence: 99%

Engineering personalized neural tissue by combining induced pluripotent stem cells with fibrin scaffolds

et al. 2015

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Induced pluripotent stem cells (iPSCs) are generated from adult somatic cells through the induction of key transcription factors that restore the ability to become any cell type found in the body. These cells are of interest for tissue engineering due to their potential for developing patient-specific therapies. As the technology for generating iPSCs advances, it is important to concurrently investigate protocols for the efficient differentiation of these cells to desired downstream phenotypes in combination with biomaterial scaffolds as a way of engineering neural tissue. For such applications, the generation of neurons within three dimensional fibrin scaffolds has been well characterized as a cell-delivery platform for murine embryonic stem cells (ESCs) but has not yet been applied to murine iPSCs. Given that iPSCs have been reported to differentiate less effectively than ESCs, a key objective of this investigation is to maximize the proportion of iPSC-derived neurons in fibrin through the choice of differentiation protocol. To this end, this study compares two EB-mediated protocols for generating neurons from murine iPSCs and ESCs: an 8-day 4-/4+ protocol using soluble retinoic acid in the last 4 days and a 6-day 2-/4+ protocol using soluble retinoic acid and the small molecule sonic hedgehog agonist purmorphamine in the last 4 days. EBs were then seeded in fibrin scaffolds for 14 days to allow further differentiation into neurons. EBs generated by the 2-/4+ protocol yielded a higher percentage of neurons compared to those from the 4-/4+ protocol for both iPSCs and ESCs. The results demonstrate the successful translation of the fibrin-based cell-delivery platform for use with murine iPSCs and furthermore that the proportion of neurons generated from murine iPSC-derived EBs seeded in fibrin can be maximized using the 2-/4+ differentiation protocol. Together, these findings validate the further exploration of 3D fibrin-based scaffolds as a method of delivering neuronal cells derived from iPSCs -an important step toward the development of iPSC-based tissue engineering strategies for spinal cord injury repair.

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“…In the present study, a weak transient outward K current was recorded in the untreated MSCs, and current significantly increased in differentiated neurons derived from MSCs. From the current-voltage curve, it was possible to determine that transient outward K current was activated at -40 mV with a strong outward rectification, which was similar electrophysiological characteristics of neurons derived from embryonic [32] and neural stem cells [33]. Similar electrophysiology characteristics have been observed in neurons derived from MSCs, although induction procedures were complicated [34] or results were obtained by co-culturing with cerebellar granule neurons [35].…”

Section: Discussionmentioning

confidence: 69%

Induction-dependent neural marker expression and electrophysiological characteristics of bone marrow mesenchymal stem cells that naturally express high levels of nestin

Liu

Wang

et al. 2011

Chin. Sci. Bull.

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Under certain experimental conditions, bone marrow mesenchymal stem cells (MSCs) express neuronal phenotypes and neuronal markers, which suggests that they could be used to treat various neurological diseases. In the present study, MSCs were isolated from adult rat bone marrow, cultivated, and evaluated for neurotrophin expression profiles, as well as the potential to differentiate into functional neuronal-like cells in vitro. MSCs from passage 5 were pre-induced with DMEM/F12 medium containing 10% fetal bovine serum (FBS) and 10 ng/mL bFGF (fibroblast growth factor-2). Subsequently, a chemical inductor containing Dimethyl Sulphoxide (DMSO), Butylated Hydroxyanisole (BHA) and forskolin were used to induce neural expression of MSCs.Expression patterns of nestin, NF-200, and GFAP at time points before and after induction were detected by immunofluorescence.Nerve Growth Factor (NGF), brain-derived neurotrophic factor (BDNF) expressions in MSCs were evaluated by RT-PCR.The whole-cell patch clamp technique was utilized to elucidate the electrical behavior of MSC before and after 24-h differentiation induction. Immunofluorescence analysis revealed that MSCs expressed nestin (57.1% ± 6.9%), but not NF-200 or GFAP. Following neural induction, the cells exhibited a neuronal-like appearance. Nestin and NF-200 expression was positive in the neuronal-like cells, but GFAP expression was negative. After 6-, 12-and 24-h induction, the ratio of nestin-positive cells was 96.5% ± 1.9%, 88.1% ± 5.4%, and 33.5% ± 5.4%. NF-200 positive cells were 90.1% ± 2.9%, 97.5% ± 1.3%, and 98.1% ± 1.6%, respectively. However, prior to induction, MSCs already expressed NGF and BDNF. With a stimulus impulse of 40 mV, the density of the transient outward K current was (9.95 ± 4.85) pA/pF (n = 9) and (328.50 ± 30.62) pA/pF (n = 9) before and after induction, and the density of transient calcium ion currents was (-0.059 ± 0.027) pA/pF (n = 7) and (-6.66 ± 0.50) pA/pF (n = 7), respectively. Transient outward potassium currents and calcium ions currents gradually increased following induction. In addition, MSCs isolated from bone marrow exhibited characteristics of neuronal progenitor cells and expressed neurotrophins. These cells exhibited the capacity to differentiate into functional neuronal-like cells in vitro. These results suggested that MSCs express high levels of nestin and could be utilized for therapeutic strategies to treat nervous system diseases.

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Functional Properties of Motoneurons Derived from Mouse Embryonic Stem Cells

Abstract: The capacity of embryonic stem (ES) cells to form functional motoneurons (MNs

Cited by 192 publications

References 61 publications

Beginning at the end: Repetitive firing properties in the final common pathway

Beginning at the end: Repetitive firing properties in the final common pathway

Engineering personalized neural tissue by combining induced pluripotent stem cells with fibrin scaffolds

Induction-dependent neural marker expression and electrophysiological characteristics of bone marrow mesenchymal stem cells that naturally express high levels of nestin

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