| 1. |
- Dunnett, Stephen B, et al.
(författare)
-
Introduction (Part I)
- 2012
-
Ingår i: Functional Neural Transplantation III : Primary and stem cell therapies for brain repair. Part 1 - Primary and stem cell therapies for brain repair. Part 1. - 0079-6123. - 9780444595751 ; 200, s. 3-5
-
Bokkapitel (refereegranskat)
|
|
| 2. |
- Dunnett, Stephen B, et al.
(författare)
-
Introduction (Part II)
- 2012
-
Ingår i: Functional Neural Transplantation III : Primary and Stem Cell Therapies for Brain Repair, Part II - Primary and Stem Cell Therapies for Brain Repair, Part II. - 0079-6123. - 9780444595447 ; 201, s. 3-5
-
Bokkapitel (refereegranskat)
|
|
| 3. |
- Thompson, Lachlan, et al.
(författare)
-
Survival, differentiation, and connectivity of ventral mesencephalic dopamine neurons following transplantation
- 2012
-
Ingår i: Functional Neural Transplantation III : Primary and Stem Cell Therapies for Brain Repair, Part I - Primary and Stem Cell Therapies for Brain Repair, Part I. - 0079-6123. - 9780444595751 ; 200, s. 61-95
-
Bokkapitel (refereegranskat)abstract
- The reconstruction of midbrain dopamine (DA) circuitry through intracerebral transplantation of new DA neurons contained in embryonic ventral mesencephalon (VM) is a promising therapeutic approach for Parkinson's disease (PD). Although some of the early open-label trials have provided proof-of-principal that VM grafts can provide sustained improvement of motor function in some patients, subsequent trials showed that the functional response can be highly variable. This chapter reviews an extensive body of basic and clinical research on the survival, differentiation, and connectivity of DA neurons in VM grafts, and also looks at how these parameters are affected by certain host- and donor-specific variables. We also review how technical advances in the tools available to study the integration of grafted DA neurons, such as transgenic reporter mice, have made significant contributions to our understanding of the capacity of different DA neuronal subtypes for target-directed growth and innervation of appropriate host brain structures. Our established and on-going understanding of the capacity of grafted DA neurons to structurally and functionally integrate following transplantation forms an important basis for the refinement and optimization of VM grafting procedures, and also the development of new procedures based on the use of stem cells.
|
|
| 4. |
- Pfisterer, Ulrich, et al.
(författare)
-
Direct conversion of human fibroblasts to dopaminergic neurons.
- 2011
-
Ingår i: Proceedings of the National Academy of Sciences. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 108:25, s. 10343-10348
-
Tidskriftsartikel (refereegranskat)abstract
- Recent reports demonstrate that somatic mouse cells can be directly converted to other mature cell types by using combined expression of defined factors. Here we show that the same strategy can be applied to human embryonic and postnatal fibroblasts. By overexpression of the transcription factors Ascl1, Brn2, and Myt1l, human fibroblasts were efficiently converted to functional neurons. We also demonstrate that the converted neurons can be directed toward distinct functional neurotransmitter phenotypes when the appropriate transcriptional cues are provided together with the three conversion factors. By combining expression of the three conversion factors with expression of two genes involved in dopamine neuron generation, Lmx1a and FoxA2, we could direct the phenotype of the converted cells toward dopaminergic neurons. Such subtype-specific induced neurons derived from human somatic cells could be valuable for disease modeling and cell replacement therapy.
|
|
| 5. |
- Björklund, Anders, et al.
(författare)
-
Gene therapy for Parkinson's disease shows promise.
- 2011
-
Ingår i: Science Translational Medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6242 .- 1946-6234. ; 3:79, s. 1-79
-
Tidskriftsartikel (refereegranskat)abstract
- A gene therapy trial for Parkinson's disease met its primary endpoint, but challenges remain.
|
|
| 6. |
- Adler, Andrew F., et al.
(författare)
-
hESC-Derived Dopaminergic Transplants Integrate into Basal Ganglia Circuitry in a Preclinical Model of Parkinson's Disease
- 2019
-
Ingår i: Cell Reports. - : Elsevier BV. - 2211-1247. ; 28:13, s. 5-3473
-
Tidskriftsartikel (refereegranskat)abstract
- Cell replacement is currently being explored as a therapeutic approach for neurodegenerative disease. Using stem cells as a source, transplantable progenitors can now be generated under conditions compliant with clinical application in patients. In this study, we elucidate factors controlling target-appropriate innervation and circuitry integration of human embryonic stem cell (hESC)-derived grafts after transplantation to the adult brain. We show that cell-intrinsic factors determine graft-derived axonal innervation, whereas synaptic inputs from host neurons primarily reflect the graft location. Furthermore, we provide evidence that hESC-derived dopaminergic grafts transplanted in a long-term preclinical rat model of Parkinson's disease (PD) receive synaptic input from subtypes of host cortical, striatal, and pallidal neurons that are known to regulate the function of endogenous nigral dopamine neurons. This refined understanding of how graft neurons integrate with host circuitry will be important for the design of clinical stem-cell-based replacement therapies for PD, as well as for other neurodegenerative diseases. Adler et al. graft hESC-derived dopaminergic progenitors into a rat model of Parkinson's disease. They find grafts correctly innervate host targets and receive appropriate synaptic input after intranigral and intrastriatal placement. Furthermore, the same host neurons projecting toward endogenous dopamine neurons are found to also connect to the grafts.
|
|
| 7. |
- Englund Johansson, Ulrica, et al.
(författare)
-
In Vivo Properties of In Vitro-Propagated Neural Stem Cells After Transplantation to the Neonatal and Adult Rat Brain
- 2004
-
Ingår i: Stem Cells in the Nervous System: Functional and Clinical Implications. Research and Perspectives in Neurosciences. - Berlin, Heidelberg : Springer. - 9783642623394 - 9783642188831
-
Konferensbidrag (refereegranskat)abstract
- The ability to isolate neural stem and precursor cells and expand them in culture has provided researchers a new tool, not only assisting studies of neural development but also providing a new source of defined and expandable cells for in vivo studies using transplantation. The purposes of this chapter are, first, to review available protocols for in vitro expansion of neural precursor cells, either epigenetically using growth factors or genetically by inserting immortalizing genes; and, second, to discuss the in vivo properties of in vitro-propagated neural stem and progenitor cells, as assessed by grafting to the developing or adult rodent brain. This discussion will focus on our own recent studies using growth factor-expanded neurosphere cells of mouse and human origin and a particularly interesting, conditionally immortalized neural cell line, RN33B.
|
|
| 8. |
- Kadkhodaei, Banafsheh, et al.
(författare)
-
Transcription factor Nurr1 maintains fiber integrity and nuclear-encoded mitochondrial gene expression in dopamine neurons
- 2013
-
Ingår i: Proceedings of the National Academy of Sciences. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 110:6, s. 2360-2365
-
Tidskriftsartikel (refereegranskat)abstract
- Developmental transcription factors important in early neuron specification and differentiation often remain expressed in the adult brain. However, how these transcription factors function to mantain appropriate neuronal identities in adult neurons and how transcription factor dysregulation may contribute to disease remain largely unknown. The transcription factor Nurr1 has been associated with Parkinson's disease and is essential for the development of ventral midbrain dopamine (DA) neurons. We used conditional Nurr1 gene-targeted mice in which Nurr1 is ablated selectively in mature DA neurons by treatment with tamoxifen. We show that Nurr1 ablation results in a progressive pathology associated with reduced striatal DA, impaired motor behaviors, and dystrophic axons and dendrites. We used laser-microdissected DA neurons for RNA extraction and next-generation mRNA sequencing to identify Nurr1-regulated genes. This analysis revealed that Nurr1 functions mainly in transcriptional activation to regulate a battery of genes expressed in DA neurons. Importantly, nuclear-encoded mitochondrial genes were identified as the major functional category of Nurr1-regulated target genes. These studies indicate that Nurr1 has a key function in sustaining high respiratory function in these cells, and that Nurr1 ablation in mice recapitulates early features of Parkinson's disease.
|
|
| 9. |
- Barker, Roger A., et al.
(författare)
-
Designing stem-cell-based dopamine cell replacement trials for Parkinson’s disease
- 2019
-
Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 25, s. 1045-1053
-
Tidskriftsartikel (refereegranskat)abstract
- Clinical studies of Parkinson’s disease (PD) using a dopamine cell replacment strategy have been tried for more than 30 years. The outcomes following transplantation of human fetal ventral mesencephalic tissue (hfVM) have been variable, with some patients coming off their anti-PD treatment for many years and others not responding and/or developing significant side effects, including graft-induced dyskinesia. This led to a re-appraisal of the best way to do such trials, which resulted in a new European-Union-funded allograft trial with fetal dopamine cells across several centers in Europe. This new trial, TRANSEURO (NCT01898390), is an open-label study in which some individuals in a large observational cohort of patients with mild PD who were undergoing identical assessments were randomly selected to receive transplants of hfVM. The TRANSEURO trial is currently ongoing as researchers have completed both recruitment into a large multicenter observational study of younger onset early-stage PD and transplantation of hfVM in 11 patients. While completion of TRANSEURO is not expected until 2021, we feel that sharing the rationale for the design of TRANSEURO, along with the lessons we have learned along the way, can help inform researchers and facilitate planning of transplants of dopamine-producing cells derived from human pluripotent stem cells for future clinical trials.
|
|
| 10. |
- Barker, Roger A, et al.
(författare)
-
The history and status of dopamine cell therapies for Parkinson's disease
-
Ingår i: BioEssays. - 0265-9247.
-
Forskningsöversikt (refereegranskat)abstract
- Parkinson's disease (PD) is characterized by the loss of the dopaminergic nigrostriatal pathway which has led to the successful development of drug therapies that replace or stimulate this network pharmacologically. Although these drugs work well in the early stages of the disease, over time they produce side effects along with less consistent clinical benefits to the person with Parkinson's (PwP). As such there has been much interest in repairing this pathway using transplants of dopamine neurons. This work which began 50 years ago this September is still ongoing and has now moved to first in human trials using human pluripotent stem cell-derived dopaminergic neurons. The results of these trials are eagerly awaited although proof of principle data has already come from trials using human fetal midbrain dopamine cell transplants. This data has shown that developing dopamine cells when transplanted in the brain of a PwP can survive long term with clinical benefits lasting decades and with restoration of normal dopaminergic innervation in the grafted striatum. In this article, we discuss the history of this field and how this has now led us to the recent stem cell trials for PwP.
|
|
