Innovations in Stem Cell Biology 2023

Synthetic mouse embryos assembled from embryonic stem cells, trophoblast stem cells and induced extraembryonic endoderm stem cells closely recapitulate the development of wild-type and mutant natural mouse embryos up to embryonic day 8.5.

Bao et al. report that a cadherin code regulates the assembly and sorting of the first three cell lineages during mammalian development and can be manipulated to enhance the efficiency of synthetic embryogenesis.

Rosebrock, Arora et al. report a method to overcome limited cortical cellular diversity in human organoids, thus mirroring fundamental features of cortical development and offering a basis for organoid-based disease modelling.

A scalable platform with geometrical reconfiguration of culture systems for long-term growth and maturation of organoids.

Engraftment of human thymic organoids supports de novo development of a functional human T cell compartment in a humanized mouse model.

A dual-channel recording system for high-resolution lineage tracing.

A method for high-content 3D imaging of organoids.

Proximal nephron in pluripotent stem cell derived kidney organoids are immature with limited support for functional solute channels. Vanslambrouck et al report improved metanephric specification, generating enhanced kidney organoids with superior proximal tubules, spatially arranged nephrons, and applications for disease research, and drug screening.

Stem cell models of organogenesis are a valuable tool for the study of human development, but often lack the context of tissue-tissue interaction. Here they generate human multi-lineage organoids comprising pro-epicardium, septum transversum, and liver bud, which they co-culture with heart organoids to generate a physiologically relevant model of organogenesis.

Since stem cells were first discovered, researchers have identified distinct stem cell populations in different organs and with various functions, converging on the unique abilities of self-renewal and differentiation toward diverse cell types. These abilities make stem cells an incredibly promising tool in therapeutics and have turned stem cell biology into a fast-evolving field. Here, stem cell biologists express their view on the most striking advances and current challenges in their field.

During development the embryo must balance lineage specification against the preservation of plasticity using a limited molecular toolkit. In this Perspective, the authors propose Molecular Versatility as a paradigm for grouping molecular mechanisms that are repurposed through development to exert distinct functions.

A protein expression atlas of transcription factors charted onto cell lineage maps of Caenorhabditis elegans development that uncovers mechanisms of spatiotemporal cell fate patterning and regulators of embryogenesis.

Single-cell RNA-sequencing of seven mouse developmental stages identifies lineage-specific and shared regulatory programs controlling cell-fate decisions. Cross-species analysis associates differentiation potency with ribosomal protein gene expression.

Transitional liver progenitor cells (TLPCs), which derive from biliary epithelial cells (BECs), differentiate into hepatocytes after serious liver damage. Notch and WNT/β-catenin signaling regulate BEC-to-TLPC and TLPC-to-hepatocyte conversions, respectively.

Disruption of MLL3/4 enzymatic activities prevents gastrulation and leads to early embryonic lethality in mice. This is largely due to defects in extraembryonic lineages, which compromise developmental progression.

Ratz et al. present an easy-to-use method to barcode progenitor cells, enabling profiling of cell phenotypes and clonal relations using single-cell and spatial transcriptomics, providing an integrated approach for understanding brain architecture.

Using zebrafish as a model, Zhang et al. show that Tmem88a/b expression is required to balance proliferation and differentiation of pharyngeal arch artery progenitors into angioblasts by confining ectodermal Wnt2bb signaling.

Relatively little is known about the first hematopoietic stem and progenitor cells to arrive in the fetal bone marrow. Here they characterize the frequency, function, and molecular identity of fetal BM HSPCs and their bone marrow niche, and show that most BM HSPCs have little hematopoietic function until birth.

The lineage relationship between blood and endothelial cells has been difficult to examine due to the multiphasic timing of hematopoiesis in the embryo. Here the authors use using in vivo barcoding technology to assess cell ancestry and show that blood and endothelial cells emerge through common (haemangioblast) or separate (mesenchymoangioblasts and haematomesoblasts) progenitors in the yolk sac.

A mathematical model of stem cell homeostasis is presented that comprehensively satisfies hierarchy and neutral competition is presented. The model predicts spontaneous generation of clonal bursts, which is consistent with primate hematopoietic data.

Mechanical compression drives activated muscle stem cells (MuSCs) into a quiescent stem cell state providing insight into MuSC activity during injury-regeneration cycles.

This review highlights the biomechanical, biophysical, and biochemical modulators of cytoskeletal remodeling during tissue neogenesis in early development and postnatal healing for targeted tissue regeneration and regenerative medicine applications.

Professor Bobby Gaspar is a distinguished physician-scientist who is a thought leader in translating basic research from bench-to-bedside and strategic work that facilitated bringing life-saving therapies to patients with rare diseases. He has over 30 years of experience in pediatric medicine working in the NHS and the biotechnology sector, and is the founding member of Orchard Therapeutics, where he serves as Chief Executive Officer. In this Q&A, Professor Gaspar provides insight into the regulatory approval and policy considerations for bringing novel therapies for rare diseases from discovery through to clinical application.

TRIM28 depletion in embryonic stem cells disconnects transcriptional condensates from super-enhancers, which is rescued by knockdown of endogenous retroviruses.

Leng et al. establish CRISPRi screens in astrocytes to dissect pathways controlling inflammatory reactivity. They uncover two distinct inflammatory reactive signatures that are inversely regulated by STAT3 and validate that these exist in human disease.

Dräger et al. establish a rapid, scalable platform for iPSC-derived microglia. CRISPRi/a screens uncover roles of disease-associated genes in phagocytosis, and regulators of disease-relevant microglial states that can be targeted pharmacologically.

The phase 3 GENESIS trial reports the superiority of the novel CXCR4 inhibitor motixafortide with G-CSF in mobilizing hematopoietic progenitor cells for autologous stem cell transplantation in multiple myeloma.

Phase 1 trial results reveal that intrathecal transplantation of human fetal neural precursor cells in patients with progressive multiple sclerosis is feasible, safe and tolerable.

A phase 1/2a study shows that human neural progenitor cells modified to release the growth factor GDNF are safely transplanted into the spinal cord of patients with ALS, with cell survival and GDNF production for over 3 years.

Injectable biomimetic hydrogels hold significant promise for tissue engineering applications. Here, the authors present a hybrid myoglobin:peptide hydrogel to overcome a critical oxygen shortage following neural stem cell transplantation, thus increasing cell survival and integration.

Current mesenchymal stem cell (MSC) transplantation practices are limited by the loss or reduced performance of MSCs. Here the authors develop a bead-jet printer for intraoperative formulation and printing of MSCs-laden Matrigel beads to improve skeletal muscle and hair follicle regeneration.

Critical-sized bone defects still present clinical challenges. Here the authors show that transplantation of neurotrophic supplement-incorporated hydrogel grafts promote full-thickness regeneration of the calvarium and perform scRNA-seq to reveal contributing stem/progenitor cells, notably a resident Msx1+ skeletal stem cell population.

Limited stem cells and mismatched interface fusion have plagued biomaterial-mediated cranial reconstruction. Here, the authors engineer an instantly fixable and self-adaptive scaffold to promote calcium chelation and interface integration, regulate macrophage M2 polarization, and recruit endogenous stem cells.

“Super-charged” NK cells kill patient-derived glioblastoma stem-like cells (GSLCs) in 2D and 3D tumor models, secrete IFN-γ and upregulate the surface expression of CD54 and MHC class I in GSLCs.

Hiramoto et al. develop a base-editing approach using SpCas9-NG, an engineered Cas9 with broad PAM flexibility, to correct a causative mutation in hemophilia B. Their approach is used to repair the point mutation in patient-derived iPSCs and restore coagulation factor IX expression in HEK293 cells and knock-in mice.

Lynggaard et al. profile the salivary proteome and metaproteome in patients with head and neck cancer who have received radiation therapy and an intraglandular mesenchymal stem cell (MSC) treatment for radiation-induced xerostomia and in healthy controls. MSC therapy impacts the composition of the salivary proteome in the longer-term.

Mouse induced pluripotent stem cells derived from differentiated fibroblasts could be converted from male (XY) to female (XX), resulting in cells that could form oocytes and give rise to offspring after fertilization.

An in vitro system that recapitulates temporal characteristics of embryonic development demonstrates that the different rates of mouse and human embryonic development stem from differences in metabolic rates and—further downstream—the global rate of protein synthesis.

Two side-by-side papers report that H3K27me3 deposited by polycomb repressive complex 2 represents an epigenetic barrier that restricts naïve human pluripotent cell differentiation into alternative lineages including trophoblasts.

Two side-by-side papers report that H3K27me3 deposited by polycomb repressive complex 2 represents an epigenetic barrier that restricts naive human pluripotent cell differentiation into alternative lineages including trophoblasts.

Xu et al. provide a single-cell transcriptomic atlas of 4–6 week human embryos, thereby profiling early human organogenesis.

Sequencing of human induced pluripotent stem cell lines highlights pervasive mutagenesis, heterogeneity between clones derived from the same individual during a single reprogramming experiment and positive selection for acquired mutations in BCOR.

Using high-resolution confocal images and computational surface mapping, Esteban et al. provide a detailed pseudodynamic atlas of early heart tube development (E7.5–E8.5), develop a morphometric staging system based on landmark curves and distances in the surface of the tissues and identify parameters that can be used for precise embryo staging across different labs. This morphometric analysis reveals early signs of left–right asymmetry, before the cardiac looping stage, which is regulated by the Nodal signaling pathway.

Destici, Zhu, et al. identify human-specific cis-regulatory elements (CREs) through a comparative epigenomic analysis of human and mouse cardiomyocytes at early stage of development and show that these CREs could contribute to species-specific cardiac features. Human-specific enhancers were particularly enriched in SNPs associated with human-specific traits (such as increased heart resting rate, atrial fibrillation and QRS duration), and the acquisition of human-specific enhancers could expand the functionality of the conserved transcriptional regulator ZIC3 by modifying its spatio-temporal expression.

Knight-Schrijver et al. use single-cell and single-nuclei RNA sequencing to profile the human fetal and adult epicardium in homeostatic conditions. The analysis shows fetal-specific epicardial gene programs that could support heart regeneration.

The development of safe preservation methods for genetic resources is important. Here, the authors successfully produce cloned mice from freeze-dried somatic cells, demonstrating the possibility of safe and low-cost preservation of genetic resources.

The human genome harbors more than 4.5 million transposable element (TE)-derived insertions, the result of recurrent waves of invasion and internal propagation. Here they show that TEs belonging to evolutionarily recent subfamilies go on to regulate later stages of human embryonic development, notably conditioning the expression of genes involved in gastrulation and early organogenesis.

iPSCs from three endangered avian species (including Okinawa rail, Japanese ptarmigan, and Blakiston’s fish owl) are developed and characterized as a potential resource for their conservation.