Novel view on hematopoietic stem cell mobilization and homing
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Conversion of placental hemogenic endothelial cells to hematopoietic stem and progenitor cells
Hematopoietic stem and progenitor cells (HSPCs) are critical for the treatment of blood diseases in clinic. However, the limited source of HSPCs severely hinders their clinical application. In the embryo, hematopoietic stem cells (HSCs) arise from hemogenic endothelial (HE) cells lining the major arteries in vivo. In this work, by engineering vascular niche endothelial cells (VN-ECs), we generated functional HSPCs in vitro from ECs at various sites, including the aorta-gonad-mesonephros (AGM) region and the placenta. Firstly, we converted mouse embryonic HE cells from the AGM region (aHE) into induced HSPCs (iHSPCs), which have the abilities for multilineage differentiation and self-renewal. Mechanistically, we found that VN-ECs can promote the generation of iHSPCs via secretion of CX3CL1 and IL1A. Next, through VN-EC co-culture, we showed that placental HE (pHE) cells, a type of extra-embryonic HE cells, were successfully converted into iHSPCs (pHE-iHSPCs), which have multilineage differentiation capacity, but exhibit limited self-renewal ability. Furthermore, comparative transcriptome analysis of aHE-iHSPCs and pHE-iHSPCs showed that aHE-iHSPCs highly expressed HSC-specific and self-renewal-related genes. Moreover, experimental validation showed that retinoic acid (RA) treatment promoted the transformation of pHE cells into iHSPCs that have self-renewal ability. Collectively, our results suggested that pHE cells possess the potential to transform into self-renewing iHSPCs through RA treatment, which will facilitate the clinical application of placental endothelial cells in hematopoietic cell generation.
Engineering bone/cartilage organoids: strategy, progress, and application
The concept and development of bone/cartilage organoids are rapidly gaining momentum, providing opportunities for both fundamental and translational research in bone biology. Bone/cartilage organoids, essentially miniature bone/cartilage tissues grown in vitro, enable the study of complex cellular interactions, biological processes, and disease pathology in a representative and controlled environment. This review provides a comprehensive and up-to-date overview of the field, focusing on the strategies for bone/cartilage organoid construction strategies, progresses in the research, and potential applications. We delve into the significance of selecting appropriate cells, matrix gels, cytokines/inducers, and construction techniques. Moreover, we explore the role of bone/cartilage organoids in advancing our understanding of bone/cartilage reconstruction, disease modeling, drug screening, disease prevention, and treatment strategies. While acknowledging the potential of these organoids, we discuss the inherent challenges and limitations in the field and propose potential solutions, including the use of bioprinting for organoid induction, AI for improved screening processes, and the exploration of assembloids for more complex, multicellular bone/cartilage organoids models. We believe that with continuous refinement and standardization, bone/cartilage organoids can profoundly impact patient-specific therapeutic interventions and lead the way in regenerative medicine.
Coupling of cell shape, matrix and tissue dynamics ensures embryonic patterning robustness
Tissue patterning coordinates morphogenesis, cell dynamics and fate specification. Understanding how precision in patterning is robustly achieved despite inherent developmental variability during mammalian embryogenesis remains a challenge. Here, based on cell dynamics quantification and simulation, we show how salt-and-pepper epiblast and primitive endoderm (PrE) cells pattern the inner cell mass of mouse blastocysts. Coupling cell fate and dynamics, PrE cells form apical polarity-dependent actin protrusions required for RAC1-dependent migration towards the surface of the fluid cavity, where PrE cells are trapped due to decreased tension. Concomitantly, PrE cells deposit an extracellular matrix gradient, presumably breaking the tissue-level symmetry and collectively guiding their own migration. Tissue size perturbations of mouse embryos and their comparison with monkey and human blastocysts further demonstrate that the fixed proportion of PrE/epiblast cells is optimal with respect to embryo size and tissue geometry and, despite variability, ensures patterning robustness during early mammalian development.
Sensory input, sex and function shape hypothalamic cell type development
Mammalian behaviour and physiology undergo major changes in early life. Young animals rely on conspecifics to meet their needs and start showing nutritional independence and sex-specific social interactions at weaning and puberty, respectively. How neuronal populations regulating homeostatic functions and social behaviours develop during these transitions remains unclear. We used paired transcriptomic and chromatin accessibility profiling to examine the developmental trajectories of neuronal populations in the hypothalamic preoptic region, where cell types with key roles in physiological and behavioural control have been identified1,2,3,4,5,6. These data show a marked diversity of developmental trajectories shaped by the sex of the animal, and the location and behavioural or physiological function of the corresponding cell types. We identify key stages of preoptic development, including early diversification, perinatal emergence of sex differences, postnatal maturation and refinement of signalling networks, and nonlinear transcriptional changes accelerating at the time of weaning and puberty. We assessed preoptic development in various sensory mutants and find a major role for vomeronasal sensing in the timing of preoptic cell type maturation. These results provide new insights into the development of neurons controlling homeostatic functions and social behaviours and lay ground for examining the dynamics of these functions in early life.
Type 2 immunity in allergic diseases
Significant advancements have been made in understanding the cellular and molecular mechanisms of type 2 immunity in allergic diseases such as asthma, allergic rhinitis, chronic rhinosinusitis, eosinophilic esophagitis (EoE), food and drug allergies, and atopic dermatitis (AD). Type 2 immunity has evolved to protect against parasitic diseases and toxins, plays a role in the expulsion of parasites and larvae from inner tissues to the lumen and outside the body, maintains microbe-rich skin and mucosal epithelial barriers and counterbalances the type 1 immune response and its destructive effects. During the development of a type 2 immune response, an innate immune response initiates starting from epithelial cells and innate lymphoid cells (ILCs), including dendritic cells and macrophages, and translates to adaptive T and B-cell immunity, particularly IgE antibody production. Eosinophils, mast cells and basophils have effects on effector functions. Cytokines from ILC2s and CD4+ helper type 2 (Th2) cells, CD8 + T cells, and NK-T cells, along with myeloid cells, including IL-4, IL-5, IL-9, and IL-13, initiate and sustain allergic inflammation via T cell cells, eosinophils, and ILC2s; promote IgE class switching; and open the epithelial barrier. Epithelial cell activation, alarmin release and barrier dysfunction are key in the development of not only allergic diseases but also many other systemic diseases. Recent biologics targeting the pathways and effector functions of IL4/IL13, IL-5, and IgE have shown promising results for almost all ages, although some patients with severe allergic diseases do not respond to these therapies, highlighting the unmet need for a more detailed and personalized approach.
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