Pacific Grove, California--Pop a few human stem cells into culture, provide the right molecular signals, and before long a mock cerebral cortex or a cerebellum knockoff could be floating in the medium. These neural, or brain, organoids, typically just a few millimeters across, are not "brains in a dish," as some journalists have described them. But they are becoming ever more sophisticated and true to life, capturing more of the brain's cellular and structural intricacy. "It's surprising how far this [area] has advanced in the last year," says John Evans, a sociologist at the University of California San Diego who follows the research and public opinions on it. That progress has allowed researchers to delve deeper into how the human brain develops, functions, and goes awry in diseases, but it has also sharpened ethical questions.

Whether or not we grow new brain cells as adults has been the subject of an ongoing and often contentious debate. Now, evidence suggests that we can. This could help answer one of neuroscience's most controversial questions and has sparked some speculation that the process could be exploited to treat conditions like depression and Alzheimer's disease. New neurons form via a process called neurogenesis in children, as well as in adult mice and macaques. This involves stem cells repeatedly giving rise to so-called progenitor cells that proliferate to form immature neurons that later become fully developed. Prior studies on human adults have identified stem cells and immature neurons in the hippocampus.

We present a foundation modeling framework that leverages deep learning to uncover latent genetic signatures across the hematopoietic hierarchy. Our approach trains a fully connected autoencoder on multipotent progenitor cells, reducing over 20,000 gene features to a 256-dimensional latent space that captures predictive information for both progenitor and downstream differentiated cells such as monocytes and lymphocytes. We validate the quality of these embeddings by training feed-forward, transformer, and graph convolutional architectures for blood disease diagnosis tasks. We also explore zero-shot prediction using a progenitor disease state classification model to classify downstream cell conditions. Our models achieve greater than 95% accuracy for multi-class classification, and in the zero-shot setting, we achieve greater than 0.7 F1-score on the binary classification task. Future work should improve embeddings further to increase robustness on lymphocyte classification specifically.

Recent advances have enabled the study of human brain development using brain organoids derived from stem cells. Quantifying cellular processes like mitosis in these organoids offers insights into neurodevelopmental disorders, but the manual analysis is time-consuming, and existing datasets lack specific details for brain organoid studies. We introduce BOrg, a dataset designed to study mitotic events in the embryonic development of the brain using confocal microscopy images of brain organoids. BOrg utilizes an efficient annotation pipeline with sparse point annotations and techniques that minimize expert effort, overcoming limitations of standard deep learning approaches on sparse data. We adapt and benchmark state-of-the-art object detection and cell counting models on BOrg for detecting and analyzing mitotic cells across prophase, metaphase, anaphase, and telophase stages. Our results demonstrate these adapted models significantly improve mitosis analysis efficiency and accuracy for brain organoid research compared to existing methods. BOrg facilitates the development of automated tools to quantify statistics like mitosis rates, aiding mechanistic studies of neurodevelopmental processes and disorders. Data and code are available at https://github.com/awaisrauf/borg.

Abstract: Accumulating evidence supports the idea that stem and progenitor cells play important roles in skeletal development. Over the last decade, the definition of skeletal stem and progenitor cells has evolved from cells simply defined by their in vitro behaviors to cells fully defined by a combination of sophisticated approaches, including serial transplantation assays and in vivo lineage-tracing experiments. These approaches have led to better identification of the characteristics of skeletal stem cells residing in multiple sites, including the perichondrium of the fetal bone, the resting zone of the postnatal growth plate, the bone marrow space and the periosteum in adulthood. These diverse groups of skeletal stem cells appear to closely collaborate and achieve a number of important biological functions of bones, including not only bone development and growth, but also bone maintenance and repair. Although these are important findings, we are only beginning to understand the diversity and the nature of skeletal stem and progenitor cells, and how they actually behave in vivo.

Hippocampal dentate granule cells are among the few neuronal cell types generated throughout adult life in mammals. In the normal brain, new granule cells are generated from progenitors in the subgranular zone and integrate in a typical fashion. During the development of epilepsy, granule cell integration is profoundly altered. The new cells migrate to ectopic locations and develop misoriented basal dendrites. Although it has been established that these abnormal cells are newly generated, it is not known whether they arise ubiquitously throughout the progenitor cell pool or are derived from a smaller number of bad actor progenitors. To explore this question, we conducted a clonal analysis study in mice expressing the Brainbow fluorescent protein reporter construct in dentate granule cell progenitors. Mice were examined 2 months after pilocarpine-induced status epilepticus, a treatment that leads to the development of epilepsy. Brain sections were rendered translucent so that entire hippocampi could be reconstructed and all fluorescently labeled cells identified. Our findings reveal that a small number of progenitors produce the majority of ectopic cells following status epilepticus, indicating that either the affected progenitors or their local microenvironments have become pathological. By contrast, granule cells with basal dendrites were equally distributed among clonal groups. This indicates that these progenitors can produce normal cells and suggests that global factors sporadically disrupt the dendritic development of some new cells. Together, these findings strongly predict that distinct mechanisms regulate different aspects