A renaissance for developmental biology driven by new in vitro platforms DOI Open Access
James M. Wells

Development, Journal Year: 2022, Volume and Issue: 149(20)

Published: Oct. 15, 2022

Over the past 30 years, I have routinely told my students that this is most exciting time in history to be a developmental biologist. This has been especially true over last decade, with emergence of new technologies and vitro platforms investigate foundational concepts biology. Special Issue Development features articles span multiple organ systems, mechanisms disease pathologies. What links these papers they all use systems provide unfettered access mammalian cells tissues. These allow for manipulation signaling gradients, biomechanical forces, genes, pathogens toxins, then live imaging, morphometry, biochemistry various omics study cell tissue behaviors. Many approaches enable studies human development were previously unimaginable. When you add our existing toolbox model we unprecedented opportunities explore biology mechanisms.There are many areas challenging but benefitted from platforms. The challenges studying early implantation- gastrulation-stage embryos linked their small size inaccessibility vivo, which limits experimental manipulations possible types readouts one can use. On top technical limitations, experiments using peri-implantation need carefully considered based on ethical guidelines. being met scale up, manipulate environmental factors (e.g. metabolites, oxygen levels), mechanical forces gene-gene interactions, dynamic fate decisions morphogenesis. Several issue highlight used embryonic development, including review synthetic embryo-like structures (Terhune et al., 2022) poster discussing assembloids (Kanton Paşca, 2022). Research cover topics such as pluripotency (Yoney 2022), embryonic-extraembryonic interactions (Vrij role hypoxia gastrulation (López-Anguita mouse endoderm formation (Medina-Cano placode (Conti Harschnitz, Pluripotent stem (PSC)-based organoid transformative organogenesis, also highlights how applied lung progenitors (Hein hippocampal (Dunville pancreatic organoids (Grapin-Botton Kim, 2022).Arguably, some uses involve mechanistically even treating diseases. There now published examples PSC-derived congenital diseases, example involves cerebral Leigh syndrome (Romero-Morales In addition, parallels between cancer (Morales Andrews, 2022; Bain One organoids, described (Niethammer identify toxins impact development. Moreover, generating therapeutics engineering transdifferentiation discussed (Huch Gouti, Tanabe Although potential generated tremendous enthusiasm, there justifiable questions accurately represent counterparts. crucial importance benchmarking samples. For example, comparing organs functionally, histologically by single RNA-sequencing. case phenotypes identified should validated samples patients. Spotlight article (Childs well Techniques Resources esophageal esophagus (Ferrer-Torres 2022).The tractability warmly embraced biomedical quantitative communities. Using engineering-inspired approaches, scientists like flow, stiffness, stretch bending behaviors, highlighted Tlili al. (2022) Munger (2022). ability quantitatively map measure behaviors imaging facilitated construction three-dimensional maps developing brain (Rodriguez-Gatica computational reconstruction neuronal networks (Räsänen biological at play during molecular luminogenesis (Lobert an unappreciated endoplasmic reticulum neural progenitor division (bin Imtiaz 2022).As final note, would point out flies, frogs, chickens, mice basic principles All unique strengths weaknesses. expanding arsenal does not diminish vivo importantly overcomes weaknesses gives us more diverse set work with. aims embrace diversity so, whatever your model, hope will consider submitting very best journal. It really

Language: Английский

Carbonic anhydrase IX: An atypical target for innovative therapies in cancer DOI Creative Commons
Roberto Ronca, Claudiu T. Supuran

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, Journal Year: 2024, Volume and Issue: 1879(4), P. 189120 - 189120

Published: May 25, 2024

Carbonic anhydrases (CAs), are metallo-enzymes implicated in several pathophysiological processes where tissue pH regulation is required. CA IX a tumor-associated isoform induced by hypoxia and involved the adaptation of tumor cells to acidosis. Indeed, tumor-driving pathways can induce expression, this turn has been associated cancer invasion metastatic features as well induction stem-like features, drug resistance recurrence. After its functional structural characterization targeting approaches have developed inhibit activity neoplastic tissues, date field seen an incredible acceleration terms therapeutic options biological readouts. Small molecules inhibitors, hybrid/dual drugs, antibodies adoptive (CAR-T based) cell therapy at preclinical level, whereas sulfonamide inhibitor antibody entered Phase Ib/II clinical trials for treatment imaging different solid tumors. Here recent advances on biology pharmacology cancer, will be discussed.

Language: Английский

Citations

28
Integrated molecular-phenotypic profiling reveals metabolic control of morphological variation in a stem-cell-based embryo model DOI Creative Commons

Alba Villaronga-Luque,

Ryan Savill, Natalia López-Anguita

et al.

Cell stem cell, Journal Year: 2025, Volume and Issue: unknown

Published: April 1, 2025

Considerable phenotypic variation under identical culture conditions limits the potential of stem-cell-based embryo models (SEMs) in basic and applied research. The biological processes causing this seemingly stochastic remain unclear. Here, we investigated roots by parallel recording transcriptomic states morphological history individual structures modeling embryonic trunk formation. Machine learning integration time-resolved single-cell RNA sequencing with imaging-based profiling identified early features predictive end states. Leveraging power revealed that imbalance oxidative phosphorylation glycolysis results aberrant morphology a neural lineage bias, which confirmed metabolic measurements. Accordingly, interventions improved Collectively, our work establishes divergent as drivers offers broadly applicable framework to chart predict organoids SEMs. strategy can be used identify control underlying processes, ultimately increasing reproducibility.

Language: Английский

Citations

2
Three‐dimensional stem cell models of mammalian gastrulation DOI Creative Commons
David A. Turner, Alfonso Martínez Arias

BioEssays, Journal Year: 2024, Volume and Issue: 46(12)

Published: Aug. 28, 2024

Abstract Gastrulation is a key milestone in the development of an organism. It period cell proliferation and coordinated cellular rearrangement, that creates outline body plan. Our current understanding mammalian gastrulation has been improved by embryo culture, but there are still many open questions difficult to address because intrauterine embryos low number specimens. In case humans, additional difficulties associated with technical ethical challenges. Over last few years, pluripotent stem models being developed have potential become useful tools understand gastrulation. Here we review these special emphasis on gastruloids provide survey methods produce them robustly, their uses, relationship embryos, prospects as well limitations.

Language: Английский

Citations

7
Hypoxia-induced cancer cell reprogramming: a review on how cancer stem cells arise DOI Creative Commons

M. Genevieve,

Madison C. Laird,

Jennifer C. Ku

et al.

Frontiers in Oncology, Journal Year: 2023, Volume and Issue: 13

Published: Aug. 8, 2023

Cancer stem cells are a subset of within the tumor that possess ability to self-renew as well differentiate into different cancer cell lineages. The exact mechanisms by which arise is still not completely understood. However, current research suggests may originate from normal have undergone genetic mutations or epigenetic changes. A more recent discovery dedifferentiation stem-like cells. These been found express and even upregulate induced pluripotent markers known Yamanaka factors. Here we discuss developments in how consider environmental factors, such hypoxia, plays key role promoting progression metastasis. Understanding give rise these could important implications for development new strategies treatments therapies.

Language: Английский

Citations

14
Neuromesodermal specification during head-to-tail body axis formation DOI
Catarina Martins‐Costa,

Valerie Wilson,

Anahí Binagui-Casas

et al.

Current topics in developmental biology/Current Topics in Developmental Biology, Journal Year: 2024, Volume and Issue: unknown, P. 232 - 271

Published: Jan. 1, 2024

Language: Английский

Citations

5
Conserved enhancers control notochord expression of vertebrate Brachyury DOI Creative Commons
Cassie L. Kemmler, Smolikova Jana, Hannah R. Moran

et al.

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Oct. 18, 2023

Abstract The cell type-specific expression of key transcription factors is central to development and disease. Brachyury/T/TBXT a major factor for gastrulation, tailbud patterning, notochord formation; however, how its controlled in the mammalian has remained elusive. Here, we identify complement notochord-specific enhancers gene. Using transgenic assays zebrafish, axolotl, mouse, discover three conserved Brachyury -controlling enhancers, T3 , C I human, marsupial genomes. Acting as Brachyury-responsive, auto-regulatory shadow cis deletion all mouse abolishes Brachyury/T/Tbxt selectively notochord, causing specific trunk neural tube defects without gastrulation or defects. -driving are beyond mammals brachyury/tbxtb loci fishes, dating their origin last common ancestor jawed vertebrates. Our data define vertebrate Brachyury/T/TBXTB through an mechanism that conveys robustness adaptability ancient basis axis development.

Language: Английский

Citations

10
Capture of Human Neuromesodermal and Posterior Neural Tube Axial Stem Cells DOI Creative Commons

Dolunay Kelle,

Enes Ugur,

Ejona Rusha

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: March 29, 2024

ABSTRACT The spinal cord, nerves, and skeletal muscles arise from neuromesodermal progenitors (NMPs). We have developed a growth-factor screening strategy, utilizing ES iPS cells, facilitating the indefinite self-renewal of two types human axial stem cells (AxSCs), closely resembling mouse NMPs (NM-AxSCs) posterior neural tube (N-AxSCs). Under specific regimens— Wnt/CHIR99021, FGF2, TGF-β inhibitor SB431542 (CFS) excluding FGF2 (CS), respectively—these AxSCs self-renew sustain telomeres. Single cell transcriptomics proteomics revealed expression growth-zone dorsoventral markers in NM-AxSCs, correspondingly, differentiation to wide spectrum neurons myocytes. N-AxSCs rapidly matured into dorsal sensory subsets crest. Crucially, neither AxSC type produces teratomas, analogous NM-AxSCs integrated successfully somites. Capturing patient GMP / without transgenesis unveils ontogeny promises modeling therapy neuropathies.

Language: Английский

Citations

3
Mannose is crucial for mesoderm specification and symmetry breaking in gastruloids DOI Creative Commons
Chaitanya Dingare, Jenny J. Yang, Benjamin Steventon

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: June 7, 2023

Abstract Patterning and growth are fundamental features of embryonic development that must be tightly coordinated during morphogenesis. As metabolism can control cell while also providing mechanistic links to developmental signalling pathways, it is ideally placed enable this coordination. To understand how impacts early mesoderm specification, we used mouse stem (ES) cell-derived gastruloids, as these temporal over metabolic manipulations generated in large quantities. Gastruloids show mosaic expression two glucose transporters, Slc2a1 Slc2a3 both which co-express with the mesodermal marker T/Bra neural Sox2 . significance cellular uptake development, inhibitor 2-deoxy-D-glucose (2-DG). 2-DG specifically blocks without affecting abolishes axial elongation gastruloids. Surprisingly, removing completely from medium did not phenocopy treatment despite a significant decline glycolytic intermediates occurring under conditions. act competitive mannose, added mannose together found could rescue specification. Together, our results crucial for pathway dispensable at stages

Language: Английский

Citations

8
Integrated Molecular-Phenotypic Profiling Reveals Metabolic Control of Morphological Variation in Stembryos DOI Creative Commons
Alba Villaronga Luque, Ryan Savill, Natalia López-Anguita

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Dec. 5, 2023

SUMMARY Mammalian stem-cell-based models of embryo development (stembryos) hold great promise in basic and applied research. However, considerable phenotypic variation despite identical culture conditions limits their potential. The biological processes underlying this seemingly stochastic are poorly understood. Here, we investigate the roots by intersecting transcriptomic states morphological history individual stembryos across stages modeling post-implantation early organogenesis. Through machine learning integration time-resolved single-cell RNA-sequencing with imaging-based quantitative profiling, identify features predictive end-state. Leveraging power revealed that imbalance oxidative phosphorylation glycolysis results aberrant morphology a neural lineage bias can be corrected metabolic interventions. Collectively, our work establishes divergent as drivers variation, offers broadly applicable framework to chart predict organoid systems. strategy leveraged control processes, ultimately increasing reproducibility vitro Highlights Time-resolved charting hundreds generates molecular fingerprints Machine identifies end-state Early cellular composition Metabolic interventions tune stembryo correct derailment differentiation outcomes

Language: Английский

Citations

8
Redox heterogeneity in mouse embryonic stem cells individualizes cell fate decisions DOI
Agnes Ulfig,

Ursula Jakob

Developmental Cell, Journal Year: 2024, Volume and Issue: 59(16), P. 2118 - 2133.e8

Published: Aug. 1, 2024

Language: Английский

Citations

2