Sažetak sa skupa
https://doi.org/10.21857/ypn4oc4189
Cerebral Organoids enable studying live surrogates of brain tissue, patient/donor specific, in long term experiments in vitro
Ante Plećaš
orcid.org/0000-0001-5839-889X
; Dept. of Anatomy and Embriology, Faculty of Veterinary Medicine, University of Zagreb, Croatia
Dinko Mitrečić
orcid.org/0000-0003-4836-1721
; Stem Cell Lab, Croatian Institute for Brain Research, Faculty of Medicine, University of Zagreb, Croatia
Ivan Alić
orcid.org/0000-0002-8125-8198
; Dept. of Anatomy and Embriology, Faculty of Veterinary Medicine, University of Zagreb, Croatia, Stem Cell Lab, Croatian Institute for Brain Research, Faculty of Medicine, University of Zagreb, Croatia, The Blizard Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, U.K.
Dean Nižetić
orcid.org/0000-0001-5486-5761
; The Blizard Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, U.K.
*
* Dopisni autor.
Sažetak
Cerebral organoids (COs) are millimeter-sized, self-organizing 3-dimensional live tissue spheres
derived from human induced pluripotent stem cells (iPSCs) differentiated into neural tissue. Standard
COs represent mixed-regions of cortical tissue, but directed organoids represent specific cellular subtypes
specific for some neuro-anatomical regions, such as dorsal forebrain cortex, hippocampus, striatum,
medial gangliomic eminence, midbrain and cerebellum. Functional connectivity between different
parts of the brain can be studied by deriving each regional organoid separately and then fusing the
parts into assembloids. Organoids were initially thought as useful models of neurodevelopmental (such
as microcephaly)1 and related disorders (such as ZIKA-virus infections causing microcephaly), but
not for conditions related to old-age neurodegeneration, due to embryonic nature of the starting cells,
and due to erasing of epigenetic ageing marks by the iPSC re-programming. Recent studies however,
including studies by Nizetic group in collaboration with Croatian Institute for Brain Research (CIBR),
uncovered that cerebral organoids, most probably due to the lack of clearing mechanisms (such as
microglia, blood-derived macrophages, glymphatics linked to circulation) surprisingly can accumulate
aggregates causative of neurogenerative conditions2,3. We and others have uncovered that organoids
can model the true causative sequence of events representing Alzheimer’s disease (AD) pathology, and
allow studies of the effects of gene dose and drugs on AD prevention, progression and spreading2.
Studying patients born with an extra-copy of the gene for the Amyloid Precursor Protein (APP) that
causes early onset Alzheimer’s disease (EOAD), including both patients with the segmental duplication
of this gene (DupAPP) and people with Down Syndrome ((DS), born with an extra copy of human
chromosome 21, harbouring the APP gene), we uncovered that their cerebral organoids develop in
just over 3 months in culture typical hallmarks of Alzheimer’s disease (AD) pathology: secretion of
toxic soluble oligomeric aggregates of β-amyloid peptide, phosphorylated Tau and inflammasome
ASC-specks3, extracellular amyloid insoluble fibrillary deposits, intracellular pathologically conformed
Tau protein, and progressive neuronal loss2. We also uncovered that the profile of β-amyloid peptides
secreted by the organoids to the culture media, closely recapitulates the profile visible in cerebrospinal
fluid of people with DS2. Importantly, all 3 pathological processes can be reversed by the inhibition of
the β-amyloid peptide, therefore recapitulating the true sequence of events in human AD: β-amyloidpeptide-
driven Tau-opathy. This is also providing the proof-of-principle that the organoid technology
can be used for drug-screening approaches to uncover compounds with potential to prevent or slowdown
AD pathogenesis2.
In other recent studies, we have shown that not only AD, but also cellular and neuronal ageing can
be modelled using COs4. We revealed that premature ageing in DS is underpinned by cellular senescence
that can be modelled in induced pluripotent stem cells (iPSCs) and cerebral organoids. We also showed that DNA damage-associated progeria, with a decrease in LaminB1 levels, is a significant
component of DS, that trisomy of the chromosome 21-encoded gene DYRK1A causes this, and that
it can be pharmacologically alleviated in iPSCs and COs4. This study included a collaboration with 6
institutions in Zagreb and was partly funded by the Croatian Science Foundation. Through this study,
a transfer of technology was achieved enabling the group at the Croatian Institute for Brain Research
(CIBR) to adopt the iPSC and COs technologies. This is now further advanced, in collaboration
with Nizetic lab in London, by producing assembloids between striatal and cortical organoids, for the
mechanistic study of neuronal connectivity defects in DS.
Our studies demonstrate that COs, despite lacking many cell types and precise 3D tissue organization
of the human brain, can model processes that mimic those in the human brain, including ageing,
neuro-inflammation and neurodegeneration. Furthermore, lack of certain brain types in organoids is
also an advantage, as it allows sequential addition of the missing cell types (such as astrocytes, microglia
or endothelial cells derived from same, or genetically altered iPSCs), and thereby the precise dissection
of the roles of each cell type in the disease being studied.
Organoid technology appears promising for the uncovering of new insights about the mechanisms,
biomarkers of disease risk and progression of prognostic significance, as well as detecting new chemical
compounds and antibodies for the developments of hitherto unknown therapeutic approaches5.
Ključne riječi
Hrčak ID:
333470
URI
Datum izdavanja:
25.6.2025.
Posjeta: 449 *