Distinct first responder cells lead the skin’s wound healing response

Under normal conditions, a menagerie of separate cell populations work to maintain skin health. However, injury prompts these isolated pools of cells to exit their individual niches and re-epithelialize the epidermis (the surface skin layer). This raises important questions about which cells react first and how the body primes them for rapid injury response.

A study by the Rompolas lab published this week in Cell Stem Cell provides a closer look at how mice maintain these pools of cells and how the cells respond after injury. Led by postdoctoral researcher Sixia Huang, the team used live cell imaging to confirm that that cells expressing Lgr6 serve as first responders that proliferate and initiate epithelial repair following injury. Moreover, the researchers show that targeted destruction of Lgr6+ cells slows the injury response by requiring other stem cells to respond.

So what makes Lgr6+ cells step up first? Consistent with previous data showing that Lgr6 expression by keratinocytes depends on skin innervation, the researchers find that sensory nerves contact the pool of Lgr6+ stem cells and are required for normal cellular dynamics post-injury. This nerve interaction regulates Lgr6+ cell identity and fate by regulating the expression of other genes within the cells, something that is drastically altered if nerves are lost.

Altogether, these results shed light on how the nervous system crosstalks with stem cells in the body. Rather than simply serve as pain receptors, cutaneous nerves prime Lgr6+ cells to function as first responders to injury. These observations may shed light on why patients suffering medical conditions associated with neuropathies, like diabetes, may also suffer from diminished wound healing.

Photo courtesy of Sixia Huang

IRM Applauds ISSCR’s Update to its Guidelines for Stem Cell Research and Clinical Translation

The Institute for Regenerative Medicine (IRM) at the University of Pennsylvania thanks the International Society for Stem Cell Research (ISSCR) for providing updated ethical guidance that covers emerging areas of the rapidly changing field of stem cell research.

As a community of regenerative biologists, engineers, and clinicians, the IRM values ethically responsible conduct of research. For years, researchers in our field have looked to the ISSCR guidelines for practical information with regard to balancing the progress of science with the moral and ethical concerns of both the scientific community and the diverse stakeholders affected by our work, including patients, policymakers, and members of the general public.

Recent breakthroughs in stem cell-based models of early human development, organoids, chimeras, and other cutting-edge research areas have warranted new attention to ethical implications. By convening international experts and respected leaders in areas of stem cell science, ethics, and law to review the latest science, the ISSCR helps researchers at institutes like ours consider the questions that arise from these new discoveries.

The IRM is committed to advancing stem cell science in an ethically responsible manner. Last November, we hosted a special Symposium on Human Development to allow members of the Penn community to learn about the new technologies and discuss their societal implications. Our scientists rigorously adhere to federal and Commonwealth of Pennsylvania conduct of research laws and the University of Pennsylvania’s ethical review systems for human and animal research. As in the past, the ISSCR guidelines will act as a supplement to these policies and a template for future discussions in our field.

IRM leadership encourages all stem cell and regenerative scientists at Penn and beyond to review the latest ISSCR guidelines and integrate them into their approaches to research.

The IRM will continue to highlight and discuss the scientific and ethical dimensions of our field as we advance regenerative medicine towards a future where patients that currently lack treatment options will have therapeutics and diagnostics based our work.

The ISSCR’s full guidelines can be found online.

The immune link between a leaky blood-brain barrier and schizophrenia

Like a stern bodyguard for the central nervous sytem, the blood-brain barrier keeps out anything that could lead to disease and dangerous inflammation—at least when all is functioning normally.

That may not be the case in people with schizophrenia and other mental disorders, suggest new findings from a team led by researchers from the School of Veterinary Medicine, Perelman School of Medicine, and Children’s Hospital of Philadelphia (CHOP). In these individuals, a more permissive barrier appears to allow the immune system to get improperly involved in the central nervous system, the researchers showed. The inflammation that arises likely contributes to the clinical manifestations of neuropsychiatric conditions.

Read more about how Jorge Alvarez, Stewart Anderson and their team used patient-derived stem cells and mouse models to examine the role of immune cells in schizophrenia in Penn Today.

Arcuate organoids to study development and disease of the hypothalamus

Human brain organoids are remarkable platforms for modeling features of human brain development and diseases. Building on methods to generate organoids to model different brain regions such as the cortex and the midbrain, researchers at the Perelman School of Medicine at the University of Pennsylvania have generated the first organoids of the arcuate nucleus (ARC), an essential structure in the hypothalamus that sends signals of hunger and feeling full. This part of the hypothalamus exhibits a tremendous amount of cell diversity, and is far more complex than previously modeled parts of the brain.

In a recent paper in Cell Stem Cell, researchers at Penn report generating arcuate organoids (ARCOs) that model the ARC of the hypothalamus. Previous studies have generated 2D hypothalamic-like neurons and 3D hypothalamic organoids from human induced pluripotent stem cells (iPSCs). However, no protocols previously existed to generate hypothalamus nucleus-specific organoids.

Read more about this work from Guo-li Ming‘s lab in Penn Medicine News.