Stem Cell-based Disease Modeling and Regenerative Therapies

We use stem cells, especially induced pluripotent stem cells, iPSCs (Fig. 1A, B), for regenerative therapies and for modelling human brain diseases. Currently, we focus on Stroke and Alzheimer’s Disease (AD), respectively.

AD is the most common type of dementia with the apolipoprotein E4 (APOE4) allele as major genetic risk factor. Using either AD patient-derived iPSCs or isogenic cells that differ only in their AD risk genes, we aim to better understand AD pathomechanisms in differentiated human cortical neurons (Fig 1C) and astrocytes (Fig. 1D).

Stroke causes a permanent disability to five million people each year. This is largely due to the lack of effective medical treatment that promotes long-term recovery. Therefore, we are developing a next-generation regenerative therapy for stroke based on transplantation of iPSC-derived cells (Fig. 1G-J).

Methods:

Induced pluripotent stem cells (iPSCs), differentiation into cortical neurons, astrocytes and neural progenitor cells, 2D and 3D cell culture, photothrombotic stroke mouse model, cell transplantation, deep neural networks (DeepLabCut), in vivo bioluminescence imaging, Laser-Doppler imaging.
 

(illustration)
(illustration)
Stem Cell-based Disease Modeling and Regenerative Therapies

A: Phase contract microscopy of an iPSC colony.

B: IPCS colony staing for plutipotency markers Nango and Tra-1-60.

C: Induced neurons from iPSCs at DIV21 are positive for the neuronal marker Map2 and display synapsin-positive presynaptic punctae.

D: IPSC-derived astrocytes expressing astrocytic marker S100β and gap junction protein connexin 43 at DIV44.

E, F: Neural progenitor cells (NPCs), derived from iPSCs, express typical marker proteins Pax6, Sox1, Nestin but not pluripotency marker Oct4. These are used for transplantation studies.

G: Laser doppler imaging showing reduced blood perfusion in the stroked hemisphere.

H: Schematic representation of DeepLabCut-based gait analysis.

I: Non-invasive in vivo bioluminescence imaging of mice transplanted with luciferase-expressing iPSC-derived NPCs, 72h after transplantation.

Images are modified from Birnbaum et al., 2018, Stem Cell Research, from de Leeuw and Tackenberg, 2019, Translational Neurodegeneration and Weber et al., 2020, Frontiers in Physiology.

Funding:

Christian Tackenberg: Swiss Commission for Technology and Innovation (CTI); Novartis Foundation for medical-biological research; University of Zurich; Olga Mayenfisch Foundation; Neuroscience Center Zurich; Betty & David Koetser Foundation for Brain Research

Ruslan Rust: Swiss National Science Foundation (SPARK)