Enhanced engraftment of human haematopoietic stem cells via mechanical remodelling mediated by the corticotropin-releasing hormone.

The engraftment of haematopoietic stem and progenitor cells (HSPCs), particularly in cord-blood transplants, remains challenging. Here we report the role of the corticotropin-releasing hormone (CRH) in enhancing the homing and engraftment of human-cord-blood HSPCs in bone marrow through mechanical remodelling. By using microfluidics, intravital two-photon imaging and long-term-engraftment assays, we show that treatment with CRH substantially enhances HSPC adhesion, motility and mechanical remodelling, ultimately leading to improved bone-marrow homing and engraftment in immunodeficient mice.

Engineered extracellular vesicles enable high-efficient delivery of intracellular therapeutic proteins.

Developing an intracellular delivery system is of key importance in the expansion of protein-based therapeutics acting on cytosolic or nuclear targets. Recently, extracellular vesicles (EVs) have been exploited as next-generation delivery modalities due to their natural role in intercellular communication and biocompatibility. However, fusion of protein of interest to a scaffold represents a widely used strategy for cargo enrichment in EVs, which could compromise the stability and functionality of cargo.

An Optimized Human Erythroblast Differentiation System Reveals Cholesterol-Dependency of Robust Production of Cultured Red Blood Cells Ex Vivo.

The generation of cultured red blood cells (cRBCs) ex vivo represents a potentially unlimited source for RBC transfusion and other cell therapies. Human cRBCs can be generated from the terminal differentiation of proliferating erythroblasts derived from hematopoietic stem/progenitor cells or erythroid precursors in peripheral blood mononuclear cells. Efficient differentiation and maturation into cRBCs highly depend on replenishing human plasma, which exhibits variable potency across donors or batches and complicates the consistent cRBC production required for clinical translation.

Wnt3a-Loaded Extracellular Vesicles Promote Alveolar Epithelial Regeneration after Lung Injury.

Compromised regeneration resulting from the deactivation of Wnt/β-catenin signaling contributes to the progression of chronic obstructive pulmonary disease (COPD) with limited therapeutic options. Extracellular cytokine-induced Wnt-based signaling provides an alternative option for COPD treatment. However, the hydrophobic nature of Wnt proteins limits their purification and use.

PEAR1 is a potential regulator of early hematopoiesis of human pluripotent stem cells.

Hemogenic endothelial (HE) cells are specialized endothelial cells to give rise to hematopoietic stem/progenitor cells during hematopoietic development. The underlying mechanisms that regulate endothelial-to-hematopoietic transition (EHT) of human HE cells are not fully understand. Here, we identified platelet endothelial aggregation receptor-1 (PEAR1) as a novel regulator of early hematopoietic development in human pluripotent stem cells (hPSCs).

Benchmarking spatial and single-cell transcriptomics integration methods for transcript distribution prediction and cell type deconvolution.

Spatial transcriptomics approaches have substantially advanced our capacity to detect the spatial distribution of RNA transcripts in tissues, yet it remains challenging to characterize whole-transcriptome-level data for single cells in space. Addressing this need, researchers have developed integration methods to combine spatial transcriptomic data with single-cell RNA-seq data to predict the spatial distribution of undetected transcripts and/or perform cell type deconvolution of spots in histological sections. However, to date, no independent studies have comparatively analyzed these integration methods to benchmark their performance.

Erythropoietic properties of human induced pluripotent stem cells-derived red blood cells in immunodeficient mice.

Transfusion of red blood cells (RBCs) is a life-saving intervention for anemic patients. Human induced pluripotent stem cells (iPSC) have the capability to expand and differentiate into RBCs (iPSC-RBCs). Here we developed a murine model to investigate the in vivo properties of human iPSC-RBCs.

gain-of-function mutation modulates the stiffness of smooth muscle cells and compromises vascular mechanics.

Heterozygous gain-of-function (GOF) mutations of hypoxia-inducible factor 2α (HIF2A), a key hypoxia-sensing regulator, are associated with erythrocytosis, thrombosis, and vascular complications that account for morbidity and mortality of patients. We demonstrated that the vascular pathology of HIF2A GOF mutations is independent of erythrocytosis. We generated HIF2A GOF-induced pluripotent stem cells (iPSCs) and differentiated them into endothelial cells (ECs) and smooth muscle cells (SMCs).

Highly efficient magnetic labelling allows MRI tracking of the homing of stem cell-derived extracellular vesicles following systemic delivery.

Human stem-cell-derived extracellular vesicles (EVs) are currently being investigated for cell-free therapy in regenerative medicine applications, but the lack of noninvasive imaging methods to track EV homing and uptake in injured tissues has limited the refinement and optimization of the approach. Here, we developed a new labelling strategy to prepare magnetic EVs (magneto-EVs) allowing sensitive yet specific MRI tracking of systemically injected therapeutic EVs. This new labelling strategy relies on the use of 'sticky' magnetic particles, namely superparamagnetic iron oxide (SPIO) nanoparticles coated with polyhistidine tags, to efficiently separate magneto-EVs from unencapsulated SPIO particles.

BMI1 enables extensive expansion of functional erythroblasts from human peripheral blood mononuclear cells.

Transfusion of red blood cells (RBCs) from ABO-matched but genetically unrelated donors is commonly used for treating anemia and acute blood loss. Increasing demand and insufficient supply for donor RBCs, especially those of universal blood types or free of known and unknown pathogens, has called for ex vivo generation of functional RBCs by large-scale cell culture. However, generating physiological numbers of transfusable cultured RBCs (cRBCs) ex vivo remains challenging, due to our inability to either extensively expand primary RBC precursors (erythroblasts) or achieve efficient enucleation once erythroblasts have been expanded and induced to differentiation and maturation.

Generation and characterization of a novel human iPSC line from a resilient Alzheimer's disease patient.

Alzheimer's disease (AD) is a progressive neurodegenerative disease that is the major cause of dementia in older people. Here, we report the derivation of human induced pluripotent stem cells (iPSCs) from an AD patient at age of 80 who has the APOE ε4/ε4 genotype and is resilient to cognitive decline for 10 years. The iPSCs reprogrammed from the blood cells of this patient by transient expression of pluripotency genes maintain the ε4/ε4 genotype, are karyotypically normal and display typical iPSC characteristics.

Human Forebrain Organoids from Induced Pluripotent Stem Cells: A Novel Approach to Model Repair of Ionizing Radiation-Induced DNA Damage in Human Neurons.

Human induced pluripotent stem cells (iPSCs) can generate virtually any cell type and therefore are applied to studies of organ development, disease modeling, drug screening and cell replacement therapy. Under proper culture conditions in vitro induced pluripotent stem cells (iPSCs) can be differentiated to form organ-like tissues, also known as "organoids", which resemble organs more closely than cells, in vivo. We hypothesized that human brain organoids can be used as an experimental model to study mechanisms underlying DNA repair in human neurons and their progenitors after radiation-induced DNA double-strand breaks (DSBs), the most severe form of DNA damage.

iPSCs from people with MS can differentiate into oligodendrocytes in a homeostatic but not an inflammatory milieu.

Multiple sclerosis (MS) is an inflammatory and demyelinating disease of the central nervous system (CNS) that results in variable severities of neurodegeneration. The understanding of MS has been limited by the inaccessibility of the affected cells and the lengthy timeframe of disease development. However, recent advances in stem cell technology have facilitated the bypassing of some of these challenges.

Transcriptional landscape of myogenesis from human pluripotent stem cells reveals a key role of TWIST1 in maintenance of skeletal muscle progenitors.

Generation of skeletal muscle cells with human pluripotent stem cells (hPSCs) opens new avenues for deciphering essential, but poorly understood aspects of transcriptional regulation in human myogenic specification. In this study, we characterized the transcriptional landscape of distinct human myogenic stages, including OCT4::EGFP+ pluripotent stem cells, MSGN1::EGFP+ presomite cells, PAX7::EGFP+ skeletal muscle progenitor cells, MYOG::EGFP+ myoblasts, and multinucleated myotubes. We defined signature gene expression profiles from each isolated cell population with unbiased clustering analysis, which provided unique insights into the transcriptional dynamics of human myogenesis from undifferentiated hPSCs to fully differentiated myotubes.

The role of mutations associated with familial neurodegenerative disorders on blood-brain barrier function in an iPSC model.

Background: Blood-brain barrier dysfunction is associated with many late-stage neurodegenerative diseases. An emerging question is whether the mutations associated with neurodegenerative diseases can independently lead to blood-brain barrier (BBB) dysfunction. Studies from patient-derived induced pluripotent stem cells suggest that mutations associated with neurodegenerative disease are non-cell autonomous, resulting in gain of toxic function in derived neurons and astrocytes.

Highly Purified Human Extracellular Vesicles Produced by Stem Cells Alleviate Aging Cellular Phenotypes of Senescent Human Cells.

Extracellular vesicles (EVs), including exosomes and microvesicles, mediate intercellular communications and exert various biological activities via delivering unique cargos of functional molecules such as RNAs and proteins to recipient cells. Previous studies showed that EVs produced and secreted by human mesenchymal stem cells (MSCs) can substitute intact MSCs for tissue repair and regeneration. In this study, we examined properties and functions of EVs from human induced pluripotent stem cells (iPSCs) that can be cultured infinitely under a chemically defined medium free of any exogenous EVs.

Human iPSC-derived blood-brain barrier microvessels: validation of barrier function and endothelial cell behavior.

Microvessels of the blood-brain barrier (BBB) regulate transport into the brain. The highly specialized brain microvascular endothelial cells, a major component of the BBB, express tight junctions and efflux transporters which regulate paracellular and transcellular permeability. However, most existing models of BBB microvessels fail to exhibit physiological barrier function.

Heterozygous IDH1 created by "single base editing" inhibits human astroglial cell growth by downregulating YAP.

Mutations in the isocitrate dehydrogenase 1 (IDH1) gene have been identified in a number of cancer types, including brain cancer. The Cancer Genome Atlas project has revealed that IDH1 mutations occur in 70-80% of grade II and grade III gliomas. Until recently, most of the functional studies of IDH1 mutations in cellular models have been conducted in overexpression systems with the IDH1 wild type background.