Efficient production of mesencephalic dopamine neurons by Lmx1a expression in embryonic stem cells

Friling, Stina; Andersson, Elisabet; Thompson, Lachlan H.; Jönsson, Marie E.; Hebsgaard, Josephine B.; Nanou, Evanthia; Alekseenko, Zhanna; Marklund, Ulrika; Kjellander, Susanna; Volakakis, Nikolaos; Hovatta, Outi; Manira, Abdeljabbar El; Björklund, Anders; Perlmann, Thomas; Ericson, Johan

doi:10.1073/pnas.0902396106

Cited by 197 publications

(181 citation statements)

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“…Using such protocols it has been possible to generate homogenous populations of specific neuronal subtypes, such as glutamatergic [47] or mesencephalic dopaminergic neurons [48]. Interestingly the spatiotemporal specification of NSCs isolated from the developing forebrain [15] can also be recapitulated in ESC in vitro systems [49,50].…”

Section: Different Protocols Have Been Established To Generate Nscs Imentioning

confidence: 99%

Stage- and area-specific control of stem cells in the developing nervous system

Falk¹,

Sommer²

2009

Current Opinion in Genetics & Development

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The spatiotemporal control of proliferation and differentiation in neural stem cells (NSCs) is essential to produce a functional nervous system (NS). Stem cells in different areas and at different time points during development have to produce different types of cells in a precise manner. Recent studies uncovered a plethora of cell extrinsic as well as intrinsic factors that play crucial roles in the area-specific and stage-specific control of NSCs. Moreover, recapitulation of the spatiotemporal specification of NSCs in vitro opens new avenues for future applications. In this review, we have selected some key molecules to discuss the mechanisms underlying the spatiotemporal regulation of NSC development. Stage-and Area-Specific Control of Stem Cells in the Developing Nervous SystemSven Falk 1 , Lukas Sommer Summary of recent advancesThe spatiotemporal control of proliferation and differentiation in neural stem cells ( In this review, we have selected some key molecules to discuss the mechanisms underlying the spatiotemporal regulation of NSC development.

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Section: Different Protocols Have Been Established To Generate Nscs Imentioning

confidence: 99%

Stage- and area-specific control of stem cells in the developing nervous system

Falk¹,

Sommer²

2009

Current Opinion in Genetics & Development

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“…So far, the most promising results have been obtained using embryonic stem (ES) cells [52][53][54][55][56][57][58][59][60][61][62] or therapeutically cloned ES cells [63]. The examples shown (Fig.…”

Section: Can Stem Cell-derived Neurons Replace Fetal Grafts In Pd Patmentioning

confidence: 99%

“…The examples shown (Fig. 4) are derived from mouse ES cells, using forced expression of the transcription factor Lmx1a, according to the protocol published by Friling et al [62] in 2009. Other types of stem cells, such as NSCs and progenitors from the embryonic ventral mesencephalon [64][65][66][67], adult NSCs from the subventricular zone [68], bone marrow stromal cells [69], and fibroblast-derived induced pluripotent stem (iPS) cells [61,[70][71][72] have also been used for this purpose.…”

Section: Can Stem Cell-derived Neurons Replace Fetal Grafts In Pd Patmentioning

confidence: 99%

“…Moreover, there is no Fig. 4 Friling et al [62] have shown that the production of midbrain dopamine (DA) neurons from mouse embryonic stem (ES) cells can be promoted by forced expression of the transcription factor Lmx1a. The DA neurons generated with this technique survive well after grafting to the rat striatum and express all the markers characteristic of authentic midbrain DA neurons.…”

Section: Toward An Effective and Safe Cell Therapy For Pdmentioning

confidence: 99%

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Cell Therapeutics in Parkinson's Disease

Lindvall

Björklund

2011

Neurotherapeutics

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The main pathology underlying motor symptoms in Parkinson's disease (PD) is a rather selective degeneration of nigrostriatal dopamine (DA) neurons. Intrastriatal transplantation of immature DA neurons, which replace those neurons that have died, leads to functional restoration in animal models of PD. Here we describe how far the clinical translation of the DA neuron replacement strategy has advanced. We briefly summarize the lessons learned from the early clinical trials with grafts of human fetal mesencephalic tissue, and discuss recent findings suggesting susceptibility of these grafts to the disease process longterm after implantation. Mechanisms underlying graftinduced dyskinesias, which constitute the only significant adverse event observed after neural transplantation, and how they should be prevented and treated are described. We summarize the attempts to generate DA neurons from stem cells of various sources and patient-specific DA neurons from fully differentiated somatic cells, with particular emphasis on the requirements of these cells to be useful in the clinical setting. The rationale for the new clinical trial with transplantation of fetal mesencephalic tissue is described. Finally, we discuss the scientific and clinical advancements that will be necessary to develop a competitive cell therapy for PD patients.

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“…After the adaptive WMT, improved efficiency in the neural networks would lead to decreased activation in the extent and magnitude of the BOLD signal in both groups. (3) Furthermore, given that WM deficits may be related to reduced dopaminergic function in HIV patients,25, 26, 27 we also explored whether polymorphisms of LIM homeobox transcription factor‐1‐alpha gene ( LMX 1A‐rs4657412), which codes for a factor that maintains dopaminergic neurons,28 would modulate the adaptive WMT effects. Polymorphisms of LMX 1A were associated with dopaminergic disorders, such as Parkinson's disease29 or schizophrenia,30 and recently with WMT effects 31.…”

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confidence: 99%

Adaptive working memory training improved brain function in human immunodeficiency virus–seropositive patients

Chang

Løhaugen

Andres

et al. 2016

Annals of Neurology

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ObjectiveWe aimed to evaluate the effectiveness of an adaptive working memory (WM) training (WMT) program, the corresponding neural correlates, and LMX1A‐rs4657412 polymorphism on the adaptive WMT, in human immunodeficiency virus (HIV) participants compared to seronegative (SN) controls.MethodsA total of 201 of 206 qualified participants completed baseline assessments before randomization to 25 sessions of adaptive WMT or nonadaptive WMT. A total of 74 of 76 (34 HIV, 42 SN) completed adaptive WMT and all 40 completed nonadaptive WMT (20 HIV, 20 SN) and were assessed after 1 month, and 55 adaptive WMT participants were also assessed after 6 months. Nontrained near‐transfer WM tests (Digit‐Span, Spatial‐Span), self‐reported executive functioning, and functional magnetic resonance images during 1‐back and 2‐back tasks were performed at baseline and each follow‐up visit, and LMX1A‐rs4657412 was genotyped in all participants.ResultsAlthough HIV participants had slightly lower cognitive performance and start index than SN at baseline, both groups improved on improvement index (>30%; false discovery rate [FDR] corrected p < 0.0008) and nontrained WM tests after adaptive WMT (FDR corrected, p ≤ 0.001), but not after nonadaptive WMT (training by training type corrected, p = 0.01 to p = 0.05) 1 month later. HIV participants (especially LMX1A‐G carriers) also had poorer self‐reported executive functioning than SN, but both groups reported improvements after adaptive WMT (Global: training FDR corrected, p = 0.004), and only HIV participants improved after nonadaptive WMT. HIV participants also had greater frontal activation than SN at baseline, but brain activation decreased in both groups at 1 and 6 months after adaptive WMT (FDR corrected, p < 0.0001), with normalization of brain activation in HIV participants, especially the LMX1A‐AA carriers (LMX1A genotype by HIV status, cluster‐corrected‐p < 0.0001).InterpretationAdaptive WMT, but not nonadaptive WMT, improved WM performance in both SN and HIV participants, and the accompanied decreased or normalized brain activation suggest improved neural efficiency, especially in HIV‐LMX1A‐AA carriers who might have greater dopaminergic reserve. These findings suggest that adaptive WMT may be an effective adjunctive therapy for WM deficits in HIV participants. ANN NEUROL 2017;81:17–34

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Efficient production of mesencephalic dopamine neurons by Lmx1a expression in embryonic stem cells

Cited by 197 publications

References 54 publications

Stage- and area-specific control of stem cells in the developing nervous system

Stage- and area-specific control of stem cells in the developing nervous system

Cell Therapeutics in Parkinson's Disease

Adaptive working memory training improved brain function in human immunodeficiency virus–seropositive patients

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