Kirigami electronics for long-term electrophysiological recording of human neural organoids and assembloids.

Realizing the full potential of organoids and assembloids to model neural development and disease will require improved methods for long-term, minimally invasive recording of electrical activity. Current technologies, such as patch clamp, penetrating microelectrodes, planar electrode arrays and substrate-attached flexible electrodes, do not allow chronic recording of organoids in suspension, which is necessary to preserve architecture. Inspired by kirigami art, we developed flexible electronics that transition from a two-dimensional to a three-dimensional basket-like configuration with either spiral or honeycomb patterns to accommodate the long-term culture of organoids in suspension.

Human assembloids.

Deconstructing and then reconstructing developmental processes ex vivo is crucial to understanding how organs assemble and how physiology can be disrupted in disease. Human 3D stem cell-derived systems, such as organoids, have facilitated this pursuit; however, they often do not capture inter-tissue or inter-lineage cellular interactions that give rise to emergent tissue properties during development. Assembloids are self-organizing 3D cellular systems that result from the integration of multiple organoids or the combination of organoids with missing cell types or primary tissue explants.

Comparison of induced neurons reveals slower structural and functional maturation in humans than in apes.

We generated induced excitatory neurons (iNeurons, iNs) from chimpanzee, bonobo, and human stem cells by expressing the transcription factor neurogenin-2 (NGN2). Single-cell RNA sequencing showed that genes involved in dendrite and synapse development are expressed earlier during iNs maturation in the chimpanzee and bonobo than the human cells. In accordance, during the first 2 weeks of differentiation, chimpanzee and bonobo iNs showed repetitive action potentials and more spontaneous excitatory activity than human iNs, and extended neurites of higher total length.

Single-cell genomic analysis of human cerebral organoids.

Investigating early brain development has previously relied on using primary developing brain tissue or two-dimensional cell culture models. Recently, stem cell-derived three-dimensional cell culture systems, collectively called brain organoids, have been developed that can faithfully recapitulate many aspects of early brain development. Together with the ability to reprogram fibroblast or blood cells into induced pluripotent stem cells from humans with neurodevelopmental disorders, this opens new inroads to study patient-specific brain development in a personalized cell culture model.

Human Stem Cell Resources Are an Inroad to Neandertal DNA Functions.

Induced pluripotent stem cells (iPSCs) from diverse humans offer the potential to study human functional variation in controlled culture environments. A portion of this variation originates from an ancient admixture between modern humans and Neandertals, which introduced alleles that left a phenotypic legacy on individual humans today. Here, we show that a large iPSC repository harbors extensive Neandertal DNA, including alleles that contribute to human phenotypes and diseases, encode hundreds of amino acid changes, and alter gene expression in specific tissues.

Single-cell-resolution transcriptome map of human, chimpanzee, bonobo, and macaque brains.

Identification of gene expression traits unique to the human brain sheds light on the molecular mechanisms underlying human evolution. Here, we searched for uniquely human gene expression traits by analyzing 422 brain samples from humans, chimpanzees, bonobos, and macaques representing 33 anatomical regions, as well as 88,047 cell nuclei composing three of these regions. Among 33 regions, cerebral cortex areas, hypothalamus, and cerebellar gray and white matter evolved rapidly in humans.

Organoid single-cell genomic atlas uncovers human-specific features of brain development.

The human brain has undergone substantial change since humans diverged from chimpanzees and the other great apes. However, the genetic and developmental programs that underlie this divergence are not fully understood. Here we have analysed stem cell-derived cerebral organoids using single-cell transcriptomics and accessible chromatin profiling to investigate gene-regulatory changes that are specific to humans.

Altered neuronal migratory trajectories in human cerebral organoids derived from individuals with neuronal heterotopia.

Malformations of the human cortex represent a major cause of disability. Mouse models with mutations in known causal genes only partially recapitulate the phenotypes and are therefore not unlimitedly suited for understanding the molecular and cellular mechanisms responsible for these conditions. Here we study periventricular heterotopia (PH) by analyzing cerebral organoids derived from induced pluripotent stem cells (iPSCs) of patients with mutations in the cadherin receptor-ligand pair DCHS1 and FAT4 or from isogenic knockout (KO) lines.

Multilineage communication regulates human liver bud development from pluripotency.

Conventional two-dimensional differentiation from pluripotency fails to recapitulate cell interactions occurring during organogenesis. Three-dimensional organoids generate complex organ-like tissues; however, it is unclear how heterotypic interactions affect lineage identity. Here we use single-cell RNA sequencing to reconstruct hepatocyte-like lineage progression from pluripotency in two-dimensional culture.

Differential transcriptional responses to Ebola and Marburg virus infection in bat and human cells.

The unprecedented outbreak of Ebola in West Africa resulted in over 28,000 cases and 11,000 deaths, underlining the need for a better understanding of the biology of this highly pathogenic virus to develop specific counter strategies. Two filoviruses, the Ebola and Marburg viruses, result in a severe and often fatal infection in humans. However, bats are natural hosts and survive filovirus infections without obvious symptoms.

Differences and similarities between human and chimpanzee neural progenitors during cerebral cortex development.

Human neocortex expansion likely contributed to the remarkable cognitive abilities of humans. This expansion is thought to primarily reflect differences in proliferation differentiation of neural progenitors during cortical development. Here, we have searched for such differences by analysing cerebral organoids from human and chimpanzees using immunohistofluorescence, live imaging, and single-cell transcriptomics.

Human cerebral organoids recapitulate gene expression programs of fetal neocortex development.

Cerebral organoids-3D cultures of human cerebral tissue derived from pluripotent stem cells-have emerged as models of human cortical development. However, the extent to which in vitro organoid systems recapitulate neural progenitor cell proliferation and neuronal differentiation programs observed in vivo remains unclear. Here we use single-cell RNA sequencing (scRNA-seq) to dissect and compare cell composition and progenitor-to-neuron lineage relationships in human cerebral organoids and fetal neocortex.

The role of gene regulatory factors in the evolutionary history of humans.

Deciphering the molecular basis of how modern human phenotypes have evolved is one of the most fascinating challenges in biology. Here, we will focus on the roles of gene regulatory factors (GRFs), in particular transcription factors (TFs) and long non-coding RNAs (lncRNAs) during human evolution. We will present examples of TFs and lncRNAs that have changed or show signs of positive selection in humans compared to chimpanzees, in modern humans compared to archaic humans, or within modern human populations.