RESEARCH

← Activated microglia (black) around amyloid plaque (blue)

iPSC-derived human microglia in the mouse brain →

Key words:

Stem Cell, Regenerative Medicine, Functional Genomics, Cell Therapy

Areas of investigation

Our laboratory combines induced pluripotent stem (iPS) cells derived from human patients and functional genomics approaches to investigate the cellular and molecular mechanisms of human neural development and the pathogenesis of neurological diseases.

For this purpose, we developed an iPS cell-based in vitro co-culture system and an in vivo human-mouse chimeric brain model to explore the mechanisms underlying neurodevelopmental disorders and age-related neurodegenerative diseases.

Human iPS cells also offer significant potential for cell therapies aimed at replacing damaged brain cells and restoring function after CNS injury. We are also focused on generating functional neurons and microglia from human iPS cells to support neural repair.

Our research forms an important link between understanding human neural development and degeneration in both health and disease and the advancement of stem cell-based therapies to treat neurological disorders.

1) In vitro neural culture: 3D spheroids / 2D triculture

Our research utilizes induced pluripotent stem (iPS) cell-derived, 2D neural triculture- and 3D spheroid model combined with CRISPR/Cas9 technology and genomic approaches such as single-cell RNA sequencing, to investigate the pathophysiology of both neurodevelopmental disorders and neurodegenerative diseases.

2) Deciphering functional mechanism of neurological diseases using chimeric model

Microglia are particularly sensitive to their cellular environment and can adopt a variety of reactive states depending on different pathological conditions, which may be difficult to mimic in vitro. Therefore, to best investigate human microglia in vivo, it would be helpful to generate mice whose endogenous microglia are replaced with human cells without the need for genetic manipulation of donor cells, which could alter microglial function.

Since the differentiation of human pluripotent stem cells provides an opportunity to develop human cellular models carrying disease gene mutations complementing existing animal models of disease, we have been developing human stem cell-derived microglia for in vivo modeling.

3) Cell therapy: Microglia replacement

Microglia have been implicated in neurodegenerative diseases, primarily due to mutations in genes expressed within microglia, such as Trem2. This suggests a link between immune response and synapse loss in neurodegenerative diseases. Consequently, targeting microglial dysfunction or replacing them with healthy donor cells emerges as a promising therapeutic option.

We have been characterizing the engraftment of microglia-like cells into the CNS to improve the efficiency of microglia replacement in non-genetic mouse models, thereby advancing the treatment of neurologcial diseases.