Targeting sonic hedgehog signaling in neurological disorders

Patel, Sita Sharan; Tomar, Sunil; Sharma, Diksha; Mahindroo, Neeraj; Malairaman, Udayabanu

doi:10.1016/j.neubiorev.2017.01.008

Cited by 68 publications

(57 citation statements)

References 326 publications

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“…SHH regulates proliferation of neural progenitor cells together with the intracellular receptor smoothened (SMO) and has neuroprotective effects. 27 Although not significant, Shh and Smo levels were also decreased (2-2.5-fold) in VWM mouse WM astrocytes. A recent study showed an impaired SHH pathway in primary astrocytes from the Eif2b5 R132H/R132H mouse, confirming the involvement of the SHH pathway in VWM.…”

Section: Discussionmentioning

confidence: 79%

Astrocyte Subtype Vulnerability in Stem Cell Models of Vanishing White Matter

Leferink

Dooves

Hillen

et al. 2019

Annals of Neurology

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Objective: Astrocytes have gained attention as important players in neurological disease. In line with their heterogeneous character, defects in specific astrocyte subtypes have been identified. Leukodystrophy vanishing white matter (VWM) shows selective vulnerability in white matter astrocytes, but the underlying mechanisms remain unclear. Induced pluripotent stem cell technology is being extensively explored in studies of pathophysiology and regenerative medicine. However, models for distinct astrocyte subtypes for VWM are lacking, thereby hampering identification of disease-specific pathways. Methods: Here, we characterize human and mouse pluripotent stem cell-derived gray and white matter astrocyte subtypes to generate an in vitro VWM model. We examined morphology and functionality, and used coculture methods, high-content microscopy, and RNA sequencing to study VWM cultures. Results: We found intrinsic vulnerability in specific astrocyte subpopulations in VWM. When comparing VWM and control cultures, white matter-like astrocytes inhibited oligodendrocyte maturation, and showed affected pathways in both human and mouse cultures, involving the immune system and extracellular matrix. Interestingly, human white matter-like astrocytes presented additional, human-specific disease mechanisms, such as neuronal and mitochondrial functioning. Interpretation: Astrocyte subtype cultures revealed disease-specific pathways in VWM. Cross-validation of human-and mouse-derived protocols identified human-specific disease aspects. This study provides new insights into VWM disease mechanisms, which helps the development of in vivo regenerative applications, and we further present strategies to study astrocyte subtype vulnerability in neurological disease.

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Section: Discussionmentioning

confidence: 79%

Astrocyte Subtype Vulnerability in Stem Cell Models of Vanishing White Matter

Leferink

Dooves

Hillen

et al. 2019

Annals of Neurology

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“…Further, VWM mouse cultures showed increased Gli1 expression, which codes for a transcription factor that is a direct target of Sonic Hedgehog (SHH) signaling. SHH regulates proliferation of neural progenitor cells together with intracellular receptor Smoothened (SMO) and has neuroprotective effects (Patel et al, 2017). While not significant, SHH and SMO levels were also decreased (2-2.5 fold) in VWM white matter-like astrocytes.…”

Section: Discussionmentioning

confidence: 99%

Human and mouse iPSC-derived astrocyte subtypes reveal vulnerability in Vanishing White Matter

Leferink

Dooves

Hillen

et al. 2019

Preprint

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Astrocytes gained attention as important players in neurological disease, including a number of leukodystrophies. Several studies explored the generation of induced pluripotent stem cell-derived astrocytes for drug screening and regenerative studies. Developing robust models of patient induced pluripotent stem cells is challenged by high variability due to diverse genetic backgrounds and long-term culture procedures. While human models are of special interest, mouse-based models have the advantage that for them these issues are less pronounced. Here we present astrocyte differentiation protocols for both human and mouse induced pluripotent stem cells to specifically induce grey and white matter astrocytes. Both subtypes expressed astrocyte-associated markers, had typical astrocyte morphologies, and gave a reactive response to stress. Importantly, the grey and white matter-like astrocytes differed in size, complexity of processes, and expression profile, conform primary grey and white matter astrocytes. The newly presented mouse and human stem cell-based models for the leukodystrophy Vanishing White Matter replicated earlier findings, such as increased proliferation, decreased OPC maturation and modulation by hyaluronidase. We studied intrinsic astrocyte subtype vulnerability in Vanishing White Matter in both human and mouse cells. Oligodendrocyte maturation was specifically inhibited in cultures with Vanishing WhiteMatter white matter-like astrocytes. By performing RNA sequencing, we found more differentially regulated genes in the white than in the grey matter-like astrocytes. Human and mouse astrocytes showed the same affected pathways, although human white matter-like astrocytes presented human-specific disease mechanisms involved in Vanishing White Matter. Using both human and mouse induced pluripotent stem cells, our study presents protocols to generate white and grey matter-like astrocytes, and shows astrocyte subtypespecific defects in Vanishing White Matter. While mouse induced pluripotent stem cell-based cultures may be less suitable to mimic human astrocyte subtype-or patient-specific changes, they might more robustly represent disease mutation-related cellular phenotypes as the cells are derived from inbred mice and the protocols are faster. The presented models give new tools to generate astrocyte subtypes for in vitro disease modeling and in vivo regenerative applications.

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“…Shh signaling regulates cell survival, proliferation, differentiation, and patterning of various areas of the brain and spinal cord (Patel, Tomar, Sharma, Mahindroo, & Udayabanu, 2017). Shh is a powerful regulator of embryonic as well as adult hippocampal neurogenesis and is required for the maintenance of adult stem cell niches (Briscoe & Th erond, 2013;Lai, Kaspar, Gage, & Schaffer, 2003;Machold et al, 2003).…”

Section: Sh H Si Gn a LI N G I N N Eu R Oge Ne Si Smentioning

confidence: 99%

Sonic hedgehog, Wnt, and brain‐derived neurotrophic factor cell signaling pathway crosstalk: potential therapy for depression

Tayyab

Shahi

Farheen

et al. 2017

J of Neuroscience Research

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There are various theories to explain the pathophysiology of depression and support its diagnosis and treatment. The roles of monoamines, brain-derived neurotrophic factor (BDNF), and Wnt signaling are well researched, but sonic hedgehog (Shh) signaling and its downstream transcription factor Gli1 are not well studied in depression. Shh signaling plays a fundamental role in embryonic development and adult hippocampal neurogenesis and also involved in the growth of cancer. In this article, we summarize the evidence for the Shh signaling pathway in depression and the potential crosstalk of Shh with Wnt and BDNF. Antidepressants are known to upregulate the adult hippocampal neurogenesis to treat depression. Shh plays an important role in adult hippocampal neurogenesis, and its downstream signaling components regulate the synthesis of Wnt proteins.

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Targeting sonic hedgehog signaling in neurological disorders

Cited by 68 publications

References 326 publications

Astrocyte Subtype Vulnerability in Stem Cell Models of Vanishing White Matter

Astrocyte Subtype Vulnerability in Stem Cell Models of Vanishing White Matter

Human and mouse iPSC-derived astrocyte subtypes reveal vulnerability in Vanishing White Matter

Sonic hedgehog, Wnt, and brain‐derived neurotrophic factor cell signaling pathway crosstalk: potential therapy for depression

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