Research achievement using iPSC-derived neurons published in the American scientific journal, iScience

A joint research of Ricoh and the University of Tokyo

March 27, 2023

TOKYO, March 27, 2023 – Ricoh's research group at the Biomedical R&D Department, led by Waka Lin, and Yuko Sekino, Project Professor at the Graduate School of Agriculture and Life Sciences, the University of Tokyo, have jointly demonstrated that transcription factor-induced human iPSC-derived neurons reach functional maturity by rapidly achieving the formation of dendritic spines and the expression of mechanisms underlying synaptic plasticity. The final version of the research article is available online at the American scientific journal iScience, updated March 23, 2023.

Dendritic spine formation and drebrin exodus in iPSC-derived neurons
Left: visualization of mature dendrites (red) and spines (green) at day 73 of culture after differentiation
Right: drebrin exits from the spines heads upon glutamate stimulation
(Scale bars: White = 100 µm. Yellow = 10 µm)

Graphical abstract summarizing the spine development and synaptic maturation process of transcription factor-induced iPSC-derived neurons

The highlights and outline of the research findings are as follows:

Highlights:

Researchers have demonstrated that transcription factor-induced iPSC-derived neurons reproduced the maturation process of human brain neurons and achieved a highly efficient formation of dendritic spines.
Successful synaptic maturation allowed the observation of drebrin exodus, a cellular mechanism underlying learning and memory, for the first time in human iPSC-derived neurons.
The mature iPSC-derived neurons generated in this study are expected to facilitate research on human synaptic functions and drug development targeting cognitive disorders.

Outline:

After induction of differentiation using a transcription factor (Note 1)-based method from Elixirgen Scientific, Inc., iPSC-derived neurons (Note 2, 3) displayed numerous dendritic spines (Note 4) in a relatively short culture time of 2 to 3 months. Time-dependent changes in gene expression patterns correlated with human brain development data and showed characteristic features of postnatal maturation, such as the conversion of drebrin (Note 5) to its brain-specific isoform (Note 6) drebrin A. Moreover, the study revealed for the first time in human iPSC neurons the conservation of the cellular event known as drebrin exodus, wherein drebrin accumulated in the spine heads migrates into dendritic shafts in response to glutamate stimulation. Drebrin exodus was previously reported to be involved in the spine structural plasticity (Note 7) of rodent primary neurons. Its observation in human neurons is of great significance for facilitating research on the maturation of human synapses and on mechanisms underlying learning and memory. Additionally, the time required for the formation of dendritic spines was reduced by one-third in transcription factor-induced iPSC neurons, which may help to reduce experimental costs substantially.

These results hold promise for a better understanding of central nervous system diseases and drug development targeting cognitive disorders. Moreover, the new opportunities raised by the availability of functionally mature human neurons would promote the iPS cell industry and the development of pharmaceutical applications, including in vitro assays for drug safety and toxicity testing.

Paper Information:

Journal: iScience

Title: Dendritic spine formation and synapse maturation in transcription factor-induced human iPSC-derived neurons

Authors: Waka Lin*, Shusaku Shiomoto, Saki Yamada, Hikaru Watanabe, Yudai Kawashima, Yuichi Eguchi, Koichi Muramatsu, and Yuko Sekino

DOI: 10.1016/j.isci.2023.106285

URL: https://doi.org/10.1016/j.isci.2023.106285

Glossary:

(Note 1): Transcription factor: A protein that initiates or regulates mRNA expression by transcribing genetic information from genomic DNA. The transcription factors expressed in a cell determine its properties and behavior.

(Note 2): iPSC-derived neurons: Neurons artificially generated in vitro by differentiating iPS cells (Note 3).

(Note 3): Induced pluripotent stem cells (iPS cells): Cells generated from somatic cells, such as human skin and blood cells, by introducing specific reprogramming factors, so that they acquire the ability to differentiate into any type of cell in the body.

(Note 4): Dendritic spines: Human and animal brain neurons form neuronal networks with axons that transmit information from one cell to another and dendrites that receive the information. Dendrites have thousands of microscopic protrusions called spines that receive signal inputs from axon terminals. Dendritic spines contain various proteins involved in memory and learning.

(Note 5): Drebrin: An actin-binding protein that stabilizes the actin fiber cytoskeleton controlling cellular morphology. The brain-specific isoform drebrin A accumulates at the postsynaptic sites and regulates the formation and dynamics of dendritic spines. Drebrin is known to exit the dendritic spines and migrate into dendritic shafts in response to excitatory stimulation, such as exposure to glutamate. This cellular mechanism, known as drebrin exodus, is essential for the induction of structural plasticity (note 7).

(Note 6): Isoform: When a single gene produces multiple proteins, each alternative protein form is referred as an isoform. One isoform may be replaced by another under specific conditions. For example, drebrin is expressed by a single gene (DBN1), but the embryonic isoform drebrin E is converted to the brain-specific isoform drebrin A during neural maturation.

(Note 7): Structural plasticity: Changes in spine shape and volume are associated with long-term changes in synaptic transmission efficiency underlying memory formation. Structural plasticity plays a crucial role in learning and forgetting mechanisms.

| About Ricoh |

Ricoh is empowering digital workplaces using innovative technologies and services that enable individuals to work smarter from anywhere.

With cultivated knowledge and organizational capabilities nurtured over its 85-year history, Ricoh is a leading provider of digital services, information management, and print and imaging solutions designed to support digital transformation and optimize business performance.

Headquartered in Tokyo, Ricoh Group has major operations throughout the world and its products and services now reach customers in approximately 200 countries and regions. In the financial year ended March 2022, Ricoh Group had worldwide sales of 1,758 billion yen (approx. 14.5 billion USD).

For further information, please visit www.ricoh.com

###

Back