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Direct reprogramming of human fibroblasts to expandable induced dopaminergic neuronal progenitors for Parkinson’s disease therapy

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE157394 | GEO | 2023/08/31

REPOSITORIES: GEO

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Direct reprogramming of human fibroblasts to expandable induced dopaminergic neuronal progenitors for Parkinson’s disease therapy [Array]

Project description:Personalized cell therapy is being explored as promising treatments for incurable diseases such as Parkinson’s disease (PD). Here, we directly reprogrammed human fibroblasts into induced dopaminergic neuronal progenitors (hiDPs) and assess their applicability for regenerative PD therapy. We found that hiDPs maintain progenitor characteristics over 20 passages and showed unaltered differentiation potential to midbrain dopaminergic neurons. By next-generation sequencing, we confirm that even long-term cultured hiDPs retain genomic stability, resulting in absence of tumorigenicity when transplanted, indicating preclinical safety. The hiDPs differentiate into highly pure dopaminergic neurons expressing markers associated with positive graft outcomes without unwanted serotonergic neurons known to cause graft-induced dyskinesia. The therapeutic effect and safety were confirmed by transplantation in rodent PD models. Because our optimized reprogramming conditions generate highly expandable hiDPs enabling scaled production of clonal cells and overcoming quality control issues, we propose that our hiDPs can become a preferred autologous therapy for aged and feeble PD patients vulnerable to immunosuppression regimens.

2023-08-31 | GSE157392 | GEO

Direct reprogramming of human fibroblasts to expandable induced dopaminergic neuronal progenitors for Parkinson’s disease therapy [ChIP-seq]

2023-08-31 | GSE157340 | GEO

Direct reprogramming of human fibroblasts to expandable induced dopaminergic neuronal progenitors for Parkinson’s disease therapy

Project description:Direct reprogramming of human fibroblasts to expandable induced dopaminergic neuronal progenitors for Parkinson’s disease therapy

| PRJNA661195 | ENA

Direct reprogramming of human fibroblasts to expandable induced dopaminergic neuronal progenitors for Parkinson’s disease therapy [Array]

Project description:Direct reprogramming of human fibroblasts to expandable induced dopaminergic neuronal progenitors for Parkinson’s disease therapy [Array]

| PRJNA661193 | ENA

Direct reprogramming of human fibroblasts to expandable induced dopaminergic neuronal progenitors for Parkinson’s disease therapy [ChIP-seq]

Project description:Direct reprogramming of human fibroblasts to expandable induced dopaminergic neuronal progenitors for Parkinson’s disease therapy [ChIP-seq]

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Direct Reprogramming to Human Induced Neuronal Progenitors from Fibroblasts of Familial and Sporadic Parkinson's Disease Patients.

Project description:In Parkinson's disease (PD) research, human neuroblastoma and immortalized neural cell lines have been widely used as in vitro models. The advancement in the field of reprogramming technology has provided tools for generating patient-specific induced pluripotent stem cells (hiPSCs) as well as human induced neuronal progenitor cells (hiNPCs). These cells have revolutionized the field of disease modeling, especially in neural diseases. Although the direct reprogramming to hiNPCs has several advantages over differentiation after hiPSC reprogramming, such as the time required and the simple procedure, relatively few studies have utilized hiNPCs. Here, we optimized the protocol for hiNPC reprogramming using pluripotency factors and Sendai virus. In addition, we generated hiNPCs of two healthy donors, a sporadic PD patient, and a familial patient with the LRRK2 G2019S mutation (L2GS). The four hiNPC cell lines are highly proliferative, expressed NPC markers, maintained the normal karyotype, and have the differentiation potential of dopaminergic neurons. Importantly, the patient hiNPCs show different apoptotic marker expression. Thus, these hiNPCs, in addition to hiPSCs, are a favorable option to study PD pathology.

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Direct reprogramming of mouse fibroblasts to neural progenitors.

Project description:The simple yet powerful technique of induced pluripotency may eventually supply a wide range of differentiated cells for cell therapy and drug development. However, making the appropriate cells via induced pluripotent stem cells (iPSCs) requires reprogramming of somatic cells and subsequent redifferentiation. Given how arduous and lengthy this process can be, we sought to determine whether it might be possible to convert somatic cells into lineage-specific stem/progenitor cells of another germ layer in one step, bypassing the intermediate pluripotent stage. Here we show that transient induction of the four reprogramming factors (Oct4, Sox2, Klf4, and c-Myc) can efficiently transdifferentiate fibroblasts into functional neural stem/progenitor cells (NPCs) with appropriate signaling inputs. Compared with induced neurons (or iN cells, which are directly converted from fibroblasts), transdifferentiated NPCs have the distinct advantage of being expandable in vitro and retaining the ability to give rise to multiple neuronal subtypes and glial cells. Our results provide a unique paradigm for iPSC-factor-based reprogramming by demonstrating that it can be readily modified to serve as a general platform for transdifferentiation.

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Direct reprogramming of human fibroblasts into dopaminergic neuron-like cells.

Project description:Transplantation of exogenous dopaminergic neuron (DA neurons) is a promising approach for treating Parkinson's disease (PD). However, a major stumbling block has been the lack of a reliable source of donor DA neurons. Here we show that a combination of five transcriptional factors Mash1, Ngn2, Sox2, Nurr1, and Pitx3 can directly and effectively reprogram human fibroblasts into DA neuron-like cells. The reprogrammed cells stained positive for various markers for DA neurons. They also showed characteristic DA uptake and production properties. Moreover, they exhibited DA neuron-specific electrophysiological profiles. Finally, they provided symptomatic relief in a rat PD model. Therefore, our directly reprogrammed DA neuron-like cells are a promising source of cell-replacement therapy for PD.

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Direct Reprogramming of Mouse Fibroblasts into Functional Skeletal Muscle Progenitors.

Project description:Skeletal muscle harbors quiescent stem cells termed satellite cells and proliferative progenitors termed myoblasts, which play pivotal roles during muscle regeneration. However, current technology does not allow permanent capture of these cell populations in vitro. Here, we show that ectopic expression of the myogenic transcription factor MyoD, combined with exposure to small molecules, reprograms mouse fibroblasts into expandable induced myogenic progenitor cells (iMPCs). iMPCs express key skeletal muscle stem and progenitor cell markers including Pax7 and Myf5 and give rise to dystrophin-expressing myofibers upon transplantation in vivo. Notably, a subset of transplanted iMPCs maintain Pax7 expression and sustain serial regenerative responses. Similar to satellite cells, iMPCs originate from Pax7+ cells and require Pax7 itself for maintenance. Finally, we show that myogenic progenitor cell lines can be established from muscle tissue following small-molecule exposure alone. This study thus reports on a robust approach to derive expandable myogenic stem/progenitor-like cells from multiple cell types.

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Direct conversion of human fibroblasts into neuronal restricted progenitors.

Project description:Neuronal restricted progenitors (NRPs) represent a type of transitional intermediate cells that lie between multipotent neural progenitors and terminal differentiated neurons during neurogenesis. These NRPs have the ability to self-renew and differentiate into neurons, but not into glial cells, which is considered an advantage for cellular therapy of human neurodegenerative diseases. However, difficulty in the extraction of highly purified NRPs from normal nervous tissue prevents further studies and applications. In this study, we report the conversion of human fetal fibroblasts into human induced NRPs (hiNRPs) in 11 days by using just three defined factors: Sox2, c-Myc, and either Brn2 or Brn4. The hiNRPs exhibited distinct neuronal characteristics, including cell morphology, multiple neuronal marker expression, self-renewal capacity, and a genome-wide transcriptional profile. Moreover, hiNRPs were able to differentiate into various terminal neurons with functional membrane properties but not glial cells. Direct generation of hiNRPs from somatic cells will provide a new source of cells for cellular replacement therapy of human neurodegenerative diseases.

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