[LUM#20] My heart stopped beating

[LUM Magazine, Podcast] - Published on October 25, 2023 in Science-Society

While the heart's reputation is well established, it is often overlooked that the proper functioning of the lungs is also dependent on a beating: that of multiciliated cells. To cure diseases affecting these essential cells, regenerative medicine researchers are tracing the cycle of life back to its origins.

A bad case of bronchitis and you find yourself "coughing your lungs out ." While this may not be a pleasant experience, it is nevertheless a sign that your bronchial tubes are working properly. To get rid of dust and germs, they secrete mucus that traps these impurities. But how do our lungs expel this mucus? "Our bronchial tubes are lined with bronchial epithelium consisting of cells whose surface is covered with cilia. By beating, these cilia direct the mucus so that it rises and is expelled," explains John De Vos, a researcher in regenerative medicine atthe IRMB . ¹. When these multiciliated cells no longer function properly, the condition is known as primary ciliary dyskinesia (PCD). These are rare and serious conditions that may require a lung transplant.

Modern alchemy

With the aim of restoring the movement of these multiciliated cells, John De Vos and Arnaud Bourdin, a pulmonologist at Montpellier University Hospital, have been working for several years on induced pluripotent stem cells, or iPS cells. "To understand iPS cells, I like to remind people that we are made up of differentiated cells, stable over time, which form either skin, bones, liver, lungs, etc." These cells begin to differentiate from the fifth or sixth day of human embryonic development. At this immature stage, they are referred to as pluripotent cells, in other words, cells capable of reproducing indefinitely and differentiating into all the types of cells that make up a human organism.

Building on the work of Shinya Yamanaka (Shinya Yamanaka, father of pluripotent stem cells, October 8, 2012, Le Monde), winner of the 2012 Nobel Prize, the two Montpellier researchers succeeded in reverting stable adult blood cells to an undifferentiated state, known as induced pluripotent cells. "From a simple blood sample taken from a patient with ciliary dyskinesia and using a fairly simple technique involving reactivating four embryonic genes, we obtain these iPS cells," explains John De Vos. These iPS cells were then placed for a week in a medium mimicking the natural environment of the embryo and "guided" to obtain lung cells. Placed in the right conditions, they will produce bronchial epithelium in about 40 days. "Sometimes I use an image of alchemy, but instead of making gold from lead, we transform blood into bronchi. ( Watch John Devos' lecture on Reprogrammed stem cells to model the bronchus at the 9th congress of the Medicine/Pharmacy Sciences Association.)

Bronchi in good condition

The goal being to replace the diseased epithelium with new, healthy epithelium, the researchers had to genetically modify the cells affected by DCP. " This work, carried out by Joffrey Mianné as part of his thesis , made it possible to repair the patient's genetic abnormality in her IPS line and create bronchial epithelium capable of beating again. " To effectively transplant this epithelium, John De Vos and his team will first have to condition the patient's bronchi. "If we deposit the repaired cells on the surface of the diseased epithelium, they risk being expelled like any other dust. We will therefore have to scrape it off, one bronchus at a time, before injecting the new cells. Animal trials will begin in the coming months, with the hope that within a few years, patients' lungs and hearts will be beating again.

1. IRMB (UM, Inserm)
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