Biology subjects

Scholer, H. R.

Publications and source records attributed to Scholer, H. R..

4 recordsLinked to original sources

bioRxiv2024

In vitro spatiotemporal reconstruction of human skeletal muscle organogenesis

Spatiotemporal recapitulation of long-range trajectories for lineages that influence body patterning along the medio-lateral and proximal-distal axes during embryogenesis in an in vitro system remains elusive. Here we introduce a three-dimensional organoid approach, termed Gastruloids-Lateraloid-Musculoids (GLMs), to model human neural crest, lateral plate mesoderm and skeletal muscle lineage development at the forelimb level following gastrulation and during limb patterning. GLMs harvest neuro-mesodermal progenitors with the potential to establish neural and paraxial mesodermal populations, while single cell analyses and spatial transcriptomics demonstrate promotion of mesodermal lineage segregation during gastrulation and spatial recapitulation of migration events along the medio-lateral axis for vagal neural crest, hypaxial myogenesis and lateral plate mesodermal lineages. Comparative analyses to developmental atlases and adult muscle stem cell data confirm a pool of hypaxial migrating myogenic progenitors that in a niche dependent manner change their embryonic anatomical developmental program to a fetal myogenic program, thus enabling them to resist specification in a cell autonomous manner and facilitate long term in vitro expansion. GLMs model human myogenesis at the forelimb level, establish fetal muscle stem cells equivalent to those that sustain the growth phase of the embryo and provide a 3D in vitro system for investigating neural crest, early fore-gut and lateral plate mesoderm development.

developmental biology↗

bioRxiv2024

Codon Pair-Specific Translation Defects Trigger Ribosome-Associated Quality Control to Avoid Proteotoxic Stress

tRNA modifications tune translation rates and codon optimality, thereby optimizing co-translational protein folding, but how codon optimality defects trigger cellular phenotypes remains unclear. Here, we show that ribosomes stall at specific modification-dependent codon pairs, triggering ribosome collisions and inducing a coordinated and hierarchical response of cellular quality control pathways. Ribosome profiling reveals an unexpected functional diversity for wobble-uridine (U34) modifications during decoding. The same modification can have different effects at the A and P sites. Furthermore, modification-dependent stalling codon pairs induce ribosome collisions, triggering ribosome-associated quality control (RQC) to prevent protein aggregation by degrading aberrant nascent peptides and mRNAs. RQC inactivation stimulates the expression of molecular chaperones to remove protein aggregates. Our results show that loss of tRNA modifications primarily disrupts translation rates of suboptimal codon pairs and reveal the coordinated regulation and adaptability of cellular surveillance systems to ensure efficient and accurate protein synthesis and maintain protein homeostasis.

biochemistry↗

bioRxiv2020

Human skeletal muscle organoids model fetal myogenesis and sustain uncommitted PAX7 myogenic progenitors

In vitro culture systems that structurally model human myogenesis and promote PAX7+ myogenic progenitor maturation have not been established. Here we report that human skeletal muscle organoids can be differentiated from induced pluripotent stem cell lines to contain paraxial mesoderm and neuromesodermal progenitors and develop into organized structures reassembling neural plate border and dermomyotome. Culture conditions instigate neural lineage arrest and promote fetal hypaxial myogenesis towards limb axial anatomical identity, with generation of sustainable uncommitted PAX7 myogenic progenitors and fibroadipogenic (PDGFRa+) progenitor populations equivalent to those from the second trimester of human gestation. Single cell comparison to human fetal and adult myogenic progenitors reveals distinct molecular signatures for non-dividing myogenic progenitors in activated (CD44High/CD98+/MYOD1+) and dormant (PAX7High/FBN1High/SPRY1High) states. Our approach provides a robust 3D in vitro developmental system for investigating muscle tissue morphogenesis and homeostasis.

bioengineering↗

bioRxiv2020

Multiple sclerosis iPSC-derived oligodendroglia conserve their intrinsic properties to functionally interact with axons and glia in vivo

The remyelination failure in multiple sclerosis (MS) is associated with a migration/differentiation block of oligodendroglia. The reason for this block is highly debated. It could result from disease-related extrinsic regulators of the oligodendroglial biology or reflect MS oligodendrocyte intrinsic properties. To avoid confounding immune-mediated extrinsic effect, we used an immune-deficient, dysmyelinating mouse model, to compare side-by-side induced pluripotent stem-cell-derived O4+ oligodendroglia from MS and healthy donors following their engraftment in the developing CNS. We show that the MS-progeny survives, proliferates and differentiates into oligodendrocytes to the same extent as controls. Quantitative multi-parametric imaging indicates that MS and control oligodendrocytes generate equal amounts of myelin, with bona-fide nodes of Ranvier and promote equal restoration of their host slow conduction. Moreover, the MS-derived progeny expressed oligodendrocyte- and astrocyte-specific connexins and established functional connections with donor and host glial cells. Thus, MS pluripotent stem cell-derived progeny fully integrates into functional axo-glial and glial-glial components, reinforcing the view that the MS oligodendrocyte differentiation block is not due to intrinsic oligodendroglial deficits. These biological findings as well as the fully integrated human-murine chimeric model should facilitate the development of pharmacological or cell-based therapies to promote CNS remyelination. One Sentence SummaryMultiple Sclerosis oligodendroglia, regardless of major immune manipulators, are intrinsically capable of myelination and making functional axo-glia and glia-glia connections after engraftment in the murine CNS, reinforcing the view that the MS oligodendrocyte differentiation block is not due to major intrinsic oligodendroglial deficits but most likely to environmental conditions.

neuroscience↗