Cell Stem Cell

Despite advances in stem cell cultures, modeling early human development with stem cells in a dish remains challenging. Research by Hislop et al.,1 Okubo et al.,2 and Wei et al.3 paves the way for improved in vitro embryo models and culture conditions, offering valuable insights for regenerative medicine.

COVID-19 patients often display dysfunctions of the nervous system, indicating an effect of SARS-CoV-2 on neural cells. Yang et al. now show that human stem-cell-derived dopaminergic neurons are susceptible to SARS-CoV-2, triggering inflammation and senescence. The study further identifies three FDA-approved drugs capable of reversing these cellular phenotypes.

3D printing human tissue models derived from stem cells provides an increasingly popular tissue engineering strategy for probing biological questions. Here Yan et al.1 demonstrate how this technology can be used to model mature human neural tissues with functional neural networks in healthy and disease states.

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The effects of exercise on fibro-adipogenic progenitors (FAPs) are unclear, and the direct molecular link is still unknown. In this study, we reveal that exercise reduces the frequency of FAPs and attenuates collagen deposition and adipose formation in injured or disused muscles through Musclin. Mechanistically, Musclin inhibits FAP proliferation and promotes apoptosis in FAPs by upregulating FILIP1L. Chromatin immunoprecipitation (ChIP)-qPCR confirms that FoxO3a is the transcription factor of FILIP1L. In addition, the Musclin/FILIP1L pathway facilitates the phagocytosis of apoptotic FAPs by macrophages through downregulating the expression of CD47...

The conjunctival epithelium covering the eye contains two main cell types: mucus-producing goblet cells and water-secreting keratinocytes, which present mucins on their apical surface. Here, we describe long-term expanding organoids and air-liquid interface representing mouse and human conjunctiva. A single-cell RNA expression atlas of primary and cultured human conjunctiva reveals that keratinocytes express multiple antimicrobial peptides and identifies conjunctival tuft cells. IL-4/-13 exposure increases goblet and tuft cell differentiation and drastically modifies the conjunctiva secretome...

The paradigmatic hematopoietic tree model is increasingly recognized to be limited, as it is based on heterogeneous populations largely defined by non-homeostatic assays testing cell fate potentials. Here, we combine persistent labeling with time-series single-cell RNA sequencing to build a real-time, quantitative model of in vivo tissue dynamics for murine bone marrow hematopoiesis. We couple cascading single-cell expression patterns with dynamic changes in differentiation and growth speeds. The resulting explicit linkage between molecular states and cellular behavior reveals widely varying self-renewal and differentiation properties across distinct lineages...

In humans, balanced invasion of trophoblast cells into the uterine mucosa, the decidua, is critical for successful pregnancy. Evidence suggests that this process is regulated by uterine natural killer (uNK) cells, but how they influence reproductive outcomes is unclear. Here, we used our trophoblast organoids and primary tissue samples to determine how uNK cells affect placentation. By locating potential interaction axes between trophoblast and uNK cells using single-cell transcriptomics and in vitro modeling of these interactions in organoids, we identify a uNK cell-derived cytokine signal that promotes trophoblast differentiation at the late stage of the invasive pathway...

COVID-19 patients commonly present with signs of central nervous system and/or peripheral nervous system dysfunction. Here, we show that midbrain dopamine (DA) neurons derived from human pluripotent stem cells (hPSCs) are selectively susceptible and permissive to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. SARS-CoV-2 infection of DA neurons triggers an inflammatory and cellular senescence response. High-throughput screening in hPSC-derived DA neurons identified several FDA-approved drugs that can rescue the cellular senescence phenotype by preventing SARS-CoV-2 infection...

All adult tissues experience wear and tear. Most tissues can compensate for cell loss through the activity of resident stem cells. Although the cellular maintenance strategies vary greatly between different adult (read: postnatal) tissues, the function of stem cells is best defined by their capacity to replace lost tissue through division. We discuss a set of six complementary hallmarks that are key enabling features of this basic function. These include longevity and self-renewal, multipotency, transplantability, plasticity, dependence on niche signals, and maintenance of genome integrity...

Human pluripotent stem cell-derived kidney organoids offer unprecedented opportunities for studying polycystic kidney disease (PKD), which still has no effective cure. Here, we developed both in vitro and in vivo organoid models of PKD that manifested tubular injury and aberrant upregulation of renin-angiotensin aldosterone system. Single-cell analysis revealed that a myriad of metabolic changes occurred during cystogenesis, including defective autophagy. Experimental activation of autophagy via ATG5 overexpression or primary cilia ablation significantly inhibited cystogenesis in PKD kidney organoids...

Stem cell therapy for Parkinson's disease requires demonstration of safety and efficacy of dopaminergic cells derived from a cell line, consideration of dose, and whether this is deliverable at scale. Park et al. demonstrate these requirements for a new hESC line and that their manufacturing methods allow for its scalability.

Research on human cerebellar development and disease has been hampered by the need for a human cell-based system that recapitulates the human cerebellum's cellular diversity and functional features. Here, we report a human organoid model (human cerebellar organoids [hCerOs]) capable of developing the complex cellular diversity of the fetal cerebellum, including a human-specific rhombic lip progenitor population that have never been generated in vitro prior to this study. 2-month-old hCerOs form distinct cytoarchitectural features, including laminar organized layering, and create functional connections between inhibitory and excitatory neurons that display coordinated network activity...

The developing human cerebellum has a greater diversity of progenitor types than that of the mouse, necessitating a human-based model for studying cerebellar development and disease. Atamian et al.1 developed a 3D organoid model of cerebellar development, which recapitulates many cell types found in the developing human cerebellum, including Purkinje-neuron-like cells.

Tissue stem-progenitor cell frequency has been implicated in tumor risk and progression, but tissue-specific factors linking these associations remain ill-defined. We observed that stiff breast tissue from women with high mammographic density, who exhibit increased lifetime risk for breast cancer, associates with abundant stem-progenitor epithelial cells. Using genetically engineered mouse models of elevated integrin mechanosignaling and collagen density, syngeneic manipulations, and spheroid models, we determined that a stiff matrix and high mechanosignaling increase mammary epithelial stem-progenitor cell frequency and enhance tumor initiation in vivo...

Using an isogenic organoid platform to model pancreatic cancer, Duan et al. establish an important link between mutant KRAS and cholesterol metabolism and identify perhexiline maleate as a possible therapeutic to target this relationship.

KRAS mutations, mainly G12D and G12V, are found in more than 90% of pancreatic ductal adenocarcinoma (PDAC) cases. The success of drugs targeting KRASG12C suggests the potential for drugs specifically targeting these alternative PDAC-associated KRAS mutations. Here, we report a high-throughput drug-screening platform using a series of isogenic murine pancreatic organoids that are wild type (WT) or contain common PDAC driver mutations, representing both classical and basal PDAC phenotypes. We screened over 6,000 compounds and identified perhexiline maleate, which can inhibit the growth and induce cell death of pancreatic organoids carrying the KrasG12D mutation both in vitro and in vivo and primary human PDAC organoids...

Stem cells are known for their resilience and enhanced activity post-stress. The mammary gland undergoes frequent remodeling and is subjected to recurring stress during the estrus cycle, but it remains unclear how mammary stem cells (MaSCs) respond to the stress and contribute to regeneration. We discovered that cytotoxic stress-induced activation of CD11c+ ductal macrophages aids stem cell survival and prevents differentiation. These macrophages boost Procr+ MaSC activity through IL1β-IL1R1-NF-κB signaling during the estrus cycle in an oscillating manner...

Our understanding of pluripotency remains limited: iPSC generation has only been established for a few model species, pluripotent stem cell lines exhibit inconsistent developmental potential, and germline transmission has only been demonstrated for mice and rats. By swapping structural elements between Sox2 and Sox17, we built a chimeric super-SOX factor, Sox2-17, that enhanced iPSC generation in five tested species: mouse, human, cynomolgus monkey, cow, and pig. A swap of alanine to valine at the interface between Sox2 and Oct4 delivered a gain of function by stabilizing Sox2/Oct4 dimerization on DNA, enabling generation of high-quality OSKM iPSCs capable of supporting the development of healthy all-iPSC mice...

Human embryonic stem cell (hESC)-derived midbrain dopaminergic (mDA) cell transplantation is a promising therapeutic strategy for Parkinson's disease (PD). Here, we present the derivation of high-purity mDA progenitors from clinical-grade hESCs on a large scale under rigorous good manufacturing practice (GMP) conditions. We also assessed the toxicity, biodistribution, and tumorigenicity of these cells in immunodeficient rats in good laboratory practice (GLP)-compliant facilities. Various doses of mDA progenitors were transplanted into hemi-parkinsonian rats, and a significant dose-dependent behavioral improvement was observed with a minimal effective dose range of 5,000-10,000 mDA progenitor cells...