Biology subjects

Shaker, M. R.

Publications and source records attributed to Shaker, M. R..

5 recordsLinked to original sources

bioRxiv2026

Oligodendrocyte Enriched Brain Organoids Reveal Impaired Oligodendroglial Maturation and Altered Neural Network Activity in Down Syndrome

Individuals with Down syndrome (DS) display developmental delay, intellectual disability, premature brain ageing, and an increased risk of Alzheimer-like neurodegeneration. Although the neuropathology of the postnatal and adult DS brain has been widely described, it remains unclear how trisomy 21 alters early human neural and glial development. Here, we used human oligodendrocyte enriched brain organoids derived from trisomic and euploid iPSCs to define the cellular, functional, and molecular consequences of trisomy 21 during early brain development. Trisomic organoids exhibited an early growth delay, reduced oligodendroglial specification, and impaired oligodendrocyte maturation, resulting in decreased myelination. These defects were accompanied by increased astroglial output and delayed neuronal maturation. At the functional level, trisomic organoids showed elevated spontaneous network activity, but failed to mount normal coordinated responses to pharmacological stimulation, consistent with abnormal neural circuit development. Bulk RNA sequencing revealed the strongest transcriptomic dysregulation occurs at early neural and glial specification. Together, these findings show that trisomy 21 disrupts early developmental stages and establish oligodendrocyte enriched brain organoids as a human model to investigate the developmental origins of white matter and network dysfunction in DS.

cell biology↗

bioRxiv2023

Choroid plexus defects in Down syndrome brain organoids enhance neurotropism of SARS-CoV-2

Why individuals with Down Syndrome (DS, trisomy 21) are particularly susceptible to SARS CoV-2 induced neuropathology remains largely unclear. Since the choroid plexus (CP) performs important barrier and immune-interface functions, secretes the cerebrospinal fluid and strongly expresses the ACE2 receptor and the chromosome 21 encoded TMPRSS2 protease, we hypothesized that the CP could play a role in establishing SARS-CoV-2 infection in the brain. To investigate the role of the choroid plexus in SARS-CoV-2 central nervous system infection in DS, we established a new type of brain organoid from DS and isogenic euploid control iPSC that consists of a core of appropriately patterned functional cortical neuronal cell types that is surrounded by a patent and functional choroid plexus (CPCOs). Remarkably, DS-CPCOs not only recapitulated abnormal features of DS cortical development but also revealed defects in ciliogenesis and epithelial cell polarity of the developing choroid plexus. We next demonstrate that the choroid plexus layer facilitates SARS-CoV-2 replication and infection of cortical neuronal cells, and that this is increased in DS-CPCOs. We further show that inhibition of TMPRSS2 and Furin activity inhibits SARS-CoV-2 replication in DS CPCOs to the level observed in euploid organoids. We conclude that CPCOs are a useful model for dissecting the role of the choroid plexus in euploid and DS forebrain development and enables screening for therapeutics that can inhibit SARS-CoV-2 induced neuro-pathogenesis.

neuroscience↗

bioRxiv2020

Human spinal cord organoids exhibiting neural tube morphogenesis for a quantifiable drug screening system of neural tube defects

The human spinal cord forms well-organized neural circuits for environment sensing and motor behavior. The three-dimensional (3D) induction of the spinal cord-like tissue from human pluripotent stem cells has been reported, but they often do not mimic morphological features of neurulation and their maturity is limited. Here, we report an advanced 3D culture system for the production of human spinal cord-like organoids (hSCOs) suitable for the scale-up and quantitative studies. The hSCOs exhibited many aspects of spinal cord development, including neurulation-like tube-forming morphogenesis, differentiation of the major spinal cord neurons and glial cells, and mature synaptic functional activities. We further demonstrated that hSCOs platform allowed quantitative and systematic high-throughput examination of the potential risk of neural tube defects induced by antiepileptic drugs. Thus, hSCOs can be used for understanding human spinal cord development, disease modeling, and toxicology screening.

cell biology↗

bioRxiv2020

Self-Organizing 3D Human Choroid Plexus-Ventricle-Cortical Organoids

Both the choroid plexus (CP) and the cortex are derived from the rostral neural tube during early embryonic development. In addition to producing CSF, the CP secretes essential factors that orchestrate cortical development and later neurogenesis. Previous brain modeling efforts with human pluripotent stem cells (hPSCs) generated either cortical or CP tissues in 3D culture. Here, we used hPSC-derived neuroectodermal cells, the building blocks of the anterior body, to simultaneously generate CP that forms ventricles and cortical cells in organoids (CVCOs), which can be maintained as 3D organoid cultures. Large scale culture revealed reproducibility of the protocol independent of cell lines, clones or batches. CVCOs contain mature and functional CP that projects multiple cilia into the ventricle-like fluid filled cysts and is in direct contact with appropriately patterned cortical cells. CVCOs thus recapitulate key features of developing forebrain structures observed in in vivo and constitute a useful for dissecting the role of CP in human forebrain development in health and disease.

neuroscience↗

bioRxiv2020

Spatiotemporal contribution of neuromesodermal progenitor-derived neural cells in the elongation of developing mouse spinal cord

During vertebrate development, the posterior end of the embryo progressively elongates in a head-to-tail direction to form the body plan. Recent lineage tracing experiments revealed that bi-potent progenitors, called neuromesodermal progenitors (NMPs), produce caudal neural and mesodermal tissues during axial elongation. However, their precise location and contribution to spinal cord development remain elusive. Here we used NMP-specific markers (Sox2 and BraT) and a genetic lineage tracing system to localize NMP progeny in vivo. NMPs were initially located at the tail tip, but were later found in the caudal neural tube, which is a unique feature of mouse development. In the neural tube, they produced neural stem cells (NSCs) and contributed to the spinal cord gradually along the AP axis during axial elongation. Interestingly, NMP-derived NSCs preferentially contributed to the ventral side first and later to the dorsal side at the lumbar spinal cord level, which may be associated with atypical junctional neurulation in mice. Our current observations detail the contribution of NMP progeny to spinal cord elongation and provide insights into how different species uniquely execute caudal morphogenesis.

developmental biology↗