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<\/a><\/p>\nResearchers in the Cao lab developed two techniques\u2014one for optics-free spatial mapping of tissue organization and the other for the enrichment of rare cell types\u2014that open new ways to study aging and disease. Image Credit: Science Photo Library<\/p>\n
That\u2019s why Rockefeller\u2019s\u00a0Junyue Cao<\/a>\u00a0has developed a suite of high-throughput single-cell genomic analysis tools that can examine how aging affects the molecular state of tens of millions of cells in the brain simultaneously.<\/p>\n Now Cao\u2019s\u00a0Laboratory of Single-Cell Genomics and Population Dynamics<\/a>\u00a0has produced two new tools and concepts for studying the molecular changes, gene expression, and intercellular dynamics of aging. In papers published in\u00a0Nature Neuroscience\u00a0and\u00a0Cell Genomics,\u00a0Cao and his team describe each of the new technologies as well as the biological insights they have already yielded.<\/p>\n \u201cThese approaches essentially take two different paths to understanding different elements of cellular dynamics and the changing molecular processes that accompany aging,\u201d says Cao.<\/p>\n Molecular neighbors<\/p>\n Cao\u2019s lab specializes in developing new techniques of high-throughput single-cell sequencing, which reveals the genetic expression and molecular dynamics of millions of individual cells simultaneously.<\/p>\n While these methods can be used for various analyses, Cao\u2019s lab focuses on aging. His team has previously used single-cell sequencing to identify\u00a0rare brain cell types<\/a>, track how\u00a0brain cells age<\/a>, pinpoint the cells\u00a0most vulnerable<\/a>\u00a0to age-related decline, and discover that aging may be a\u00a0developmental stage\u00a0<\/a>triggered by specific molecular cues.<\/p>\n The two new approaches Cao\u2019s lab has developed, IRISeq and EnrichSci, tackle cellular aging from different angles.<\/p>\n IRISeq capitalizes on recent discoveries showing that DNA can act like a kind of molecular barcode or even a ruler, recording which molecules are close to one another, says Abdulraouf Abdul, an M.D.-Ph.D. student in Cao\u2019s lab. \u201cFor centuries, scientists have relied on microscopes to study tissues and understand how cells are organized. We wondered, could DNA itself be used to map entire tissues without using a microscope at all?\u201d<\/p>\n The technique was designed to do just that. In work led by Abdul and Weirong Jiang, a research associate in the Cao lab, the team developed an optics-free, high-throughput approach that uses millions of barcoded, micrometer-sized beads to capture local gene expression information across tissue. The beads exchange DNA-based signals with nearby beads, allowing researchers to piece together where cells are located in the tissue\u2014and all without a microscope. Abdul and his colleagues\u00a0described the work<\/a>\u00a0in\u00a0Nature Neuroscience.<\/p>\n \u201cWith IRISeq, we can rebuild the layout of tissues at different levels of detail\u2014almost like zooming in and out on a map\u2014without ever taking a single picture. That means we can study very large pieces of tissues or many tissue sections in a way that would be much harder or more expensive to do with traditional imaging methods,\u201d he says. \u201cIn essence, we turned sequencing into a new way of \u2018seeing\u2019 biology at a fraction of the cost.\u201d<\/p>\n Adds Cao, \u201cWe can use this map interaction to see how the cells are driven by their external cell interactions during the aging process. It can probe the interactions of virtually any two\u2014or more\u2014types of cells anywhere in the brain at the same time.\u201d<\/p>\n Using this approach, the team mapped inflammatory cellular neighborhoods in the aging brain. They found that inflammatory subtypes of microglia, oligodendrocytes, and astrocytes tend to cluster together in white matter and interact with one another. These findings suggest that white matter may be a particularly vulnerable region of the aging brain where disease-associated cellular states emerge and reinforce each other.<\/p>\n For example, they found that immune cells called lymphocytes play a major role in driving inflammation in the aging brain in a very specific way.<\/p>\n \u201cTheir activity is concentrated in certain regions, especially near the brain\u2019s fluid-filled spaces known as ventricles,\u201d Abdul says. \u201cWithout spatial information, this kind of localized immune activity would have been easy to miss.\u201d<\/p>\n \u201cKnowing both the types of cells that cluster together and where they do so can provide potential targets for anti-aging interventions,\u201d Cao says.<\/p>\n Changes in unexpected places<\/p>\n