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Chronobiology – timing processes in tissues

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How tissues communicate to achieve synchrony

Microscopic images of human bone cancer cells showing a fluorescent reporter (green nucleus). Control cells (top) show robust synchronized reporter activity over time. In contrast, cells treated with a TGF-ß coupling inhibitor  (bottom) show weaker, non-synchronized oscillations. © Charité | Adrián E. Granada
Microscopic images of human bone cancer cells showing a fluorescent reporter (green nucleus). Control cells (top) show robust synchronized reporter activity over time. In contrast, cells treated with a TGF-ß coupling inhibitor (bottom) show weaker, non-synchronized oscillations. © Charité | Adrián E. Granada

The body’s circadian clocks enable organs and organ systems to function according to finely tuned daily rhythms. In humans and other mammals, these circadian rhythms are controlled by an area of the brain known as the hypothalamus. Researchers from Charité – Universitätsmedizin Berlin have deciphered an additional, previously unknown mechanism which is responsible for synchrony at the cellular level and plays a crucial role in maintaining rhythmic organ function. Writing in Science Advances*, the researchers describe the ways in which peripheral circadian clocks (circadian clocks found in cells outside the brain) communicate in order to generate a coherent rhythm at the tissue-level.

Nearly all cells in the human body have their own circadian clocks which are responsible for controlling and coordinating the timing of important organ functions. The circadian rhythms produced by these biological clocks differ slightly from cell to cell. In order to achieve synchrony, these cells therefore have to communicate with one another. “An absence of this intercellular information exchange can result in the timing of important biological tissue functions being disrupted. One possible result of this is an increase in the risk of metabolic disorders,” explains study lead Prof. Dr. Achim Kramer, Head of Chronobiology at Charité’s Institute of Medical Immunology. While intercellular communication within the suprachiasmatic nucleus, a key area of the brain’s hypothalamus responsible for synchronizing our internal clocks with the diurnal pattern of light and darkness, is relatively well understood, the synchronization of internal clocks within the body’s other tissues remains somewhat of a mystery. The team of researchers led by Prof. Kramer therefore set out to study whether (and in what way) peripheral internal clocks interact using a process known as ‘coupling’ in order to synchronize their rhythms.

Using cell-based models of different tissues, the researchers examined the nature of the biological mechanisms underlying this communication and explored what impact the disruption of this synchronization might have on cell aggregates. “To produce our measurements of cellular rhythms, we used ‘reporter genes’ which generate either bioluminescent or fluorescent signals. With their help, we were able to study whether cellular internal clocks are capable of adapting their rhythms to achieve synchrony with others,” says the study’s first author Dr. Anna-Marie Finger, a chronobiologist at Charité’s Institute of Medical Immunology. Working alongside Dr. Robert Hurwitz from the Max Planck Institute for Infection Biology, the team then used chromatography- and mass spectrometry-based methods to identify protein factors which facilitate internal clock synchronization. “We found that these cellular clocks communicate with each other using proteins produced for this purpose. The cells release ‘Transforming growth factor beta’ (TGF-ß) which drives the synchronization of these internal clocks by controlling the production of the core regulator protein PER2,” says Dr. Finger. She adds: “The use of pharmacological and genetic means to disrupt the TGF-ß signaling pathway resulted in reduced circadian rhythmicity at both the cellular and tissue levels and rendered internal clocks more susceptible to external disruptors.” This observation shows just how crucial the identified communication pathway is for internal clock synchrony at the cellular level and, hence, for the timing of organ function.

“The disruption of internal clock coupling might perturb the timing of important biological tissue functions which, in turn, could promote pathological processes,” explains Prof. Kramer. “An inadequate synchronization of pancreatic alpha and beta cells, for instance, could result in the natural rhythm of glucagon and insulin production being disrupted, thus facilitating diabetes-related disorders.” The researchers will now use further models to study the intercellular communication of internal clocks in vivo. The aim is to ascertain which rhythmic processes are affected in different tissues when the TGF-ß signaling pathway is disrupted. The researchers hope to gain insights into the potential impact of misaligned internal clocks on disease development.

*Finger AM et al. Intercellular coupling between peripheral circadian oscillators by TGF-β signaling. Sci Adv (2021), doi: 10.1126/sciadv.abg5174


Original article

Institute of Medical Immunology – Chronobiology Unit

Video (Vimeo): Cells with synchronous cellular rhythm (control cells) © Charité | Adrian E. Granada

Video (Vimeo): Cells with asynchronous cellular rhythms (TGF-β coupling inhibited) © Charité | Adrian E. Granada

The videos can be made available as files on request.


Prof. Dr. Achim Kramer
Institute for Medical Immunology
Charité – Universitätsmedizin Berlin
Tel: +49 30 450 524 263

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