Similar Datasets
Project description:First-in-human clinical trials illustrate the feasibility and translational potential of human pluripotent stem cell (hPSC)-based cell therapy in Parkinson’s disease (PD). However, a major unresolved challenge is the extensive cell death following transplantation with <10% of grafted dopamine neurons surviving. Here, we performed a pooled CRISPR/Cas9 screen to enhance survival of postmitotic dopamine neurons in vivo. We identified TP53-mediated apoptotic cell death as major contributor to dopamine neuron loss and uncovered a causal link of TNFa-NFκB signaling in limiting cell survival. A surface marker screen enabled the purification of midbrain dopamine neurons obviating the need for genetic reporters. Combining cell sorting with adalimumab pretreatment, a clinically approved TNFa inhibitor, enabled efficient engraftment of postmitotic dopamine neurons leading to extensive re-innervation and functional recovery in a preclinical PD mouse model. Thus, transient TNFa inhibition may present a clinically relevant strategy to enhance survival of human PSC-derived lineages in PD and beyond.
2024-04-26 | GSE217131 | GEO
Project description:First-in-human clinical trials illustrate the feasibility and translational potential of human pluripotent stem cell (hPSC)-based cell therapy in Parkinson’s disease (PD). However, a major unresolved challenge is the extensive cell death following transplantation with <10% of grafted dopamine neurons surviving. Here, we performed a pooled CRISPR/Cas9 screen to enhance survival of postmitotic dopamine neurons in vivo. We identified TP53-mediated apoptotic cell death as major contributor to dopamine neuron loss and uncovered a causal link of TNFa-NFκB signaling in limiting cell survival. A surface marker screen enabled the purification of midbrain dopamine neurons obviating the need for genetic reporters. Combining cell sorting with adalimumab pretreatment, a clinically approved TNFa inhibitor, enabled efficient engraftment of postmitotic dopamine neurons leading to extensive re-innervation and functional recovery in a preclinical PD mouse model. Thus, transient TNFa inhibition may present a clinically relevant strategy to enhance survival of human PSC-derived lineages in PD and beyond.
2024-04-26 | GSE216364 | GEO
Project description:Cas9 screen to enhance survival of postmitotic dopamine neurons in vivo. We identified TP53-mediated apoptotic cell death as major contributor to dopamine neuron loss and uncovered a causal link of TNFa-NFκB signaling in limiting cell survival. A surface marker screen enabled the purification of midbrain dopamine neurons obviating the need for genetic reporters. Combining cell sorting with adalimumab pretreatment, a clinically approved TNFa inhibitor, enabled efficient engraftment of postmitotic dopamine neurons leading to extensive re-innervation and functional recovery in a preclinical PD mouse model. Thus, transient TNFa inhibition may present a clinically relevant strategy to enhance survival of human PSC-derived lineages in PD and beyond.
2024-04-26 | GSE216363 | GEO
Project description:TNF-NFkB-p53 axis restricts in vivo survival of hPSC-derived dopamine neuron
| PRJNA893219 | ENA
Project description:TNF-NFkB-p53 axis restricts in vivo survival of hPSC-derived dopamine neuron (scRNA-Seq)
| PRJNA893221 | ENA
Project description:TNF-NFkB-p53 axis restricts in vivo survival of hPSC-derived dopamine neuron (RNA-Seq)
| PRJNA893220 | ENA
Project description:TNF-NFkB-p53 axis restricts in vivo survival of hPSC-derived dopamine neuron (CRISPR screen)
| PRJNA896993 | ENA
Project description:Common disorders, including diabetes and Parkinson's disease, are caused by a combination of environmental factors and genetic susceptibility. However, defining the mechanisms underlying gene-environment interactions has been challenging due to the lack of a suitable experimental platform. Using pancreatic β-like cells derived from human pluripotent stem cells (hPSCs), we discovered that a commonly used pesticide, propargite, induces pancreatic β-cell death, a pathological hallmark of diabetes. Screening a panel of diverse hPSC-derived cell types we extended this observation to a similar susceptibility in midbrain dopamine neurons, a cell type affected in Parkinson's disease. We assessed gene-environment interactions using isogenic hPSC lines for genetic variants associated with diabetes and Parkinson's disease. We found GSTT1-/- pancreatic β-like cells and dopamine neurons were both hypersensitive to propargite-induced cell death. Our study identifies an environmental chemical that contributes to human β-cell and dopamine neuron loss and validates a novel hPSC-based platform for determining gene-environment interactions.
| S-EPMC6240096 | biostudies-literature
Project description:BackgroundAlzheimer's disease is the most common cause of dementia and is characterized by amyloid-β plaques, tau neurofibrillary tangles, and neuronal loss. Although neuronal loss is a primary hallmark of Alzheimer's disease, it is known that non-neuronal cell populations are ultimately responsible for maintaining brain homeostasis and neuronal health through neuron-glia and glial cell crosstalk. Many signaling pathways have been proposed to be dysregulated in Alzheimer's disease, including WNT, TGFβ, p53, mTOR, NFkB, and Pi3k/Akt signaling. Here, we predict altered cell-cell communication between glia and neurons.MethodsUsing public snRNA-sequencing data generated from postmortem human prefrontal cortex, we predicted altered cell-cell communication between glia (astrocytes, microglia, oligodendrocytes, and oligodendrocyte progenitor cells) and neurons (excitatory and inhibitory). We confirmed interactions in an independent orthogonal dataset. We determined cell-type-specificity using Jaccard Similarity Index and investigated the downstream effects of altered interactions in inhibitory neurons through gene expression and transcription factor activity analyses of signaling mediators. Finally, we determined changes in pathway activity in inhibitory neurons.ResultsCell-cell communication between glia and neurons is altered in Alzheimer's disease in a cell-type-specific manner. As expected, ligands are more cell-type-specific than receptors and targets. We validated 51 ligand-receptor pairs in an independent dataset that included two known Alzheimer's disease risk genes: APP and APOE. 17 (14 upregulated and 3 downregulated in Alzheimer's disease) of the 51 interactions also had the same downstream target gene. Most of the signaling mediators of these interactions were not differentially expressed, however, the mediators that are also transcription factors had differential activity between AD and control. Namely, MYC and TP53, which are associated with WNT and p53 signaling, respectively, had repressor activity in Alzheimer's disease, along with decreased WNT and p53 activity in inhibitory neurons. Additionally, inhibitory neurons had both increased NFkB signaling pathway activity and activator activity of NFIL3, an NFkB signaling-associated transcription factor.ConclusionsCell-cell communication between glia and neurons in Alzheimer's disease is altered in a cell-type-specific manner involving Alzheimer's disease risk genes. Signaling mediators had altered transcription factor activity suggesting altered glia-neuron interactions may dysregulate signaling pathways including WNT, p53, and NFkB in inhibitory neurons.
| S-EPMC10705421 | biostudies-literature
Project description:Midbrain dopamine (MbDA) neurons are partitioned into medial and lateral cohorts that control complex functions. However, the genetic underpinnings of MbDA neuron heterogeneity are unclear. While it is known that Wnt1-expressing progenitors contribute to MbDA neurons, the role of Wnt1 in MbDA neuron development in vivo is unresolved. We show that mice with a spontaneous point mutation in Wnt1 have a unique phenotype characterized by the loss of medial MbDA neurons concomitant with a severe depletion of Wnt1-expressing progenitors and diminished LMX1a-expressing progenitors. Wnt1 mutant embryos also have alterations in a hierarchical gene regulatory loop suggesting multiple gene involvement in the Wnt1 mutant MbDA neuron phenotype. To investigate this possibility, we conditionally deleted Gbx2, Fgf8, and En1/2 after their early role in patterning and asked whether these genetic manipulations phenocopied the depletion of MbDA neurons in Wnt1 mutants. The conditional deletion of Gbx2 did not result in re-positioning or distribution of MbDA neurons. The temporal deletion of Fgf8 did not result in the loss of either LMX1a-expressing progenitors nor the initial population of differentiated MbDA neurons, but did result in a complete loss of MbDA neurons at later stages. The temporal deletion and species specific manipulation of En1/2 demonstrated a continued and species specific role of Engrailed genes in MbDA neuron development. Notably, our conditional deletion experiments revealed phenotypes dissimilar to Wnt1 mutants indicating the unique role of Wnt1 in MbDA neuron development. By placing Wnt1, Fgf8, and En1/2 in the context of their temporal requirement for MbDA neuron development, we further deciphered the developmental program underpinning MbDA neuron progenitors.
| S-EPMC3502751 | biostudies-literature