June brings us to the fourth edition of our blog series, the MaxWell Monthly Must-Reads. This month’s selection of articles will focus on induced pluripotent stem cells or iPSCs. This technology, developed by researchers at Kyoto University lead by Dr. Shinya Yamanaka, allows adult cells to be genetically ‘reprogrammed’ to a stem cell-like state. Thus, it is possible to derive specific cell types from iPSCs, such as neurons and cardiomyocytes, providing a means to study human cells in-vitro. Increasingly, iPSCs are being used as a tool for disease modeling, drug discovery, and regenerative medicine. MaxWell Biosystems’ platforms are currently used by investigators around the world to analyze the function and maturity of iPSC-derived neurons. Included in this month’s must-reads are the latest exciting works related to the development of disease models from patients and characterization of different types of iPSC-derived neurons.
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- Hyperexcitable phenotypes in iPSC-derived neurons from patients with 15q11-q13 duplication syndrome, a genetic form of autism
by James J Fink, Jeremy D Schreiner, Judy E Bloom, Dylan S Baker, Tiwanna M Robinson, Richard Lieberman, Leslie M Loew, Stormy J Chamberlain and Eric Levine. Preprint in bioRxiv. March 2018.
This work analyzed the hyperexcitability of neurons derived from iPSC lines from patients with chromosome 15q11-q13 duplication syndrome (Dup15q). Dup15q patients experience seizures and are considered to meet the criteria for autism spectrum disorder (ASD). Using whole-cell patch clamp on cultures (week 3-20 after plating), the authors show that iPSC-derived neurons from Dup15q patient cell lines exhibit high rates of spontaneous action potentials compared to control cells. Similarly, both the frequency and amplitude of spontaneous synaptic events were significantly higher in Dup15q neurons compared to controls. These results provide phenotypes associated with Dup15q that can potentially be targeted by treatments.
Read the paper here.
- Hyperexcitable phenotypes in iPSC-derived neurons from patients with 15q11-q13 duplication syndrome, a genetic form of autism
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- Kv7 channels are upregulated during striatal neuron development and promote maturation of human iPSC-derived neurons
by Vsevolod Telezhkin, Marco Straccia, Polina Yarova, Monica Pardo, Sun Yung, Ngoc-Nga Vinh, Jane M. Hancock, Gerardo Garcia-Diaz Barriga, David A. Brown, Anne E. Rosser, Jonathan T. Brown, Josep M. Canals, Andrew D. Randall, Nicholas D. Allen, Paul J. Kemp. European Journal of Physiology. May 2018.
The authors show that regulated expression of Kv7 channels (KNCQ) is crucial to the maturation of both mouse striatal neurons and human iPSC-derived neurons. Kv7 are voltage-gated potassium ion channels that are involved in maintaining the resting membrane potential and excitability of neurons. The findings of this work provide insights on future investigations of neuronal development, modeled in-vitro by stem cell technology,
Read the paper here.
- Kv7 channels are upregulated during striatal neuron development and promote maturation of human iPSC-derived neurons
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- Astrocytes attenuate mitochondrial dysfunctions in human dopaminergic neurons derived from iPSC
by Fang Du, Qing Yu, Allen Chen, Doris Chen and Shirley ShiDu Yan. CellPress. February 2018.
This research investigated the role of astrocytes on the development of human iPSC-derived dopaminergic neurons by means of co-culturing. It was found that astrocytes restore mitochondrial function in defective dopaminergic neurons disrupted by mitochondrial toxins. The co-culture provided a model for future studies of mitochondrial involvement during development and disease.
Read the paper here.
- Astrocytes attenuate mitochondrial dysfunctions in human dopaminergic neurons derived from iPSC
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- Modeling down syndrome with patient IPSCs reveals cellular and migration deficits of GABAergic neurons
by Hai-Qin Huo, Zhuang-Yin Qu, Fang Yuan, Lixiang Ma, Lin Yao, Min Xu, Yao Hu, Jing Ji, Anita Bhattacharyya, Su-Chun Zhang and Yan Liu. CellPress. April 2018.
Down syndrome (DS) is the most common genetic disorder of intellectual impairment. This work used iPSC lines from DS patients to derive GABAergic neurons in order to analyze differences compared to healthy control cells. The authors found that DS GABAergic interneurons have smaller soma size, shortened neurite length, and reduced branching complexity compared to controls. Additionally, DS GABA interneurons exhibited altered subtypes and decreased migration in-vitro and in-vivo. These results explain the reduced number of interneurons in DS patients’ brains, potentially contributing to impaired cognition.
Read the paper here.
- Modeling down syndrome with patient IPSCs reveals cellular and migration deficits of GABAergic neurons
- Super-Obese Patient-Derived iPSC hypothalamic neurons exhibit obesogenic signatures and hormone responses.
by Uthra Rajamani, Andrew R. Gross, Brooke E. Hjelm, Adolfo Sequeira, Marquis P. Vawter, Jie Tang, Vineela Gangalapudi, Yizhou Wang, Allen M. Andres, Roberta A. Gottlieb and Dhruv Sareen. Cell Press. May 2018.
Neurons from the hypothalamus secrete neuropeptides that regulate feeding behavior in response to hunger hormone ghrelin and satiety endocrine signals. In order to study this response in obesity, Sareen and colleagues generated hypothalamic-like neurons from super-obese patient iPSCs and analyzed them for phenotypes likely related to obesity. The super-obese iPSC-derived hypothalamic neurons retained dysregulated obesogenic disease signatures despite undergoing the reprogramming process, and exhibited abnormal response to ghrelin compared to control cells. This work presents a functional in-vitro platform to study obesity, which could be used for screening potential therapies.
Read the paper here. More information can be found here and here.
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