Culture shock

Immune Cells Forget Culture (Cell) Shock

image: Alveolar macrophages are the immune cells that specifically live in the alveoli of the lungs, seen here as red dots in an otherwise transparent mouse lung.
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Credit: Sara Gholamhosseinian Najjar and Michaela Burkon

Macrophages are crucial immune cells for immune response, tissue repair, and elimination of cancer cells. Scientists see macrophages as promising living therapies. However, to be used effectively for therapeutic purposes, macrophages must be grown in large numbers in laboratory culture without losing their particular functions. Until now, it was unclear if this was even possible. A team of scientists from Dresden and Marseilles now reports that macrophages cultured for long periods of time under laboratory conditions can function normally when transferred into the body and are indistinguishable from cells that have never left the tissue. The results pave the way for new cell therapies based on macrophages. The study was published in the journal Natural immunology on February 24, 2022.

Macrophages are immune cells present in all organs of our body. They act as tissue guardians, nourishing other cells and eliminating harmful substances such as bacteria, cellular debris and even tumor cells. Consequently, macrophages have been on the radar of scientists as potential new living drugs to heal damaged organs, fight infections, and fight cancer. However, to achieve this, the cells must be grown in large numbers outside the body. So far, this has been difficult for macrophages. On top of that, there were serious doubts that the lab conditions might cause them to lose their special abilities.

Multiplication of cells in the laboratory, called cell culture, is a common technique that over the years has led to enormous advances in biology and medicine. Nevertheless, the cells cultured in the laboratory are removed from their natural environment and from the physical signals that seem essential to their functioning. The cells are cultured on plastic culture dishes and bathed in artificial nutrient solutions. They have to adapt to these new conditions, a real culture shock. “We wanted to know exactly how cells change in prolonged cell culture and whether these changes are permanent or not,” says Professor Michael Sieweke, Humboldt Professor at TU Dresden.

Cell culture shock

Pr Sieweke’s team from the Dresden Regenerative Therapy Center (CRTD) of the TU Dresden and the Marseille Luminy Immunology Center (CNRS, INSERM, Aix-Marseille University) studied mouse lung macrophages, immune cells which naturally live in the air sacs of the lung. The team managed to grow the cells under laboratory conditions for several months and in large numbers. Although their general appearance and characteristics were unaffected, when examined more closely it became clear that the cells had in fact acquired many changes to adapt to the new environment.

“Every cell in our body has the same set of genes, but cells differ in which genes are turned on and which are turned off. It can be thought of as the molecular fingerprint of the cell – a unique combination of activated genes that distinguish, for example, a lung macrophage from an intestinal macrophage and a brain cell,” explains Sethuraman Subramanian, one of the authors of the study. . Scientists compared the genetic pattern of lab-grown cells with their lung counterparts and found substantial differences. “It was to be expected. Living on a plastic surface and having all the nutrients readily available is quite different from natural conditions. The cells had to get used to it and did so by altering the status of over 3,000 genes. The question that really interested us was whether these changes could be reversed,” says Professor Sieweke.

forget the culture

The team transferred the lab-grown macrophages to their natural location in the mouse lungs. Detailed comparisons showed that cells grown in the laboratory were indistinguishable from their counterparts that never left the lung. “We were surprised to see that the substantial adaptations that macrophages made to life in the laboratory turned out to be completely reversible. The lab-grown macrophages had forgotten their time in the lab and fully assumed their normal function and status in the lungs, unaware of their previous culture shock,” says Clara Busch, one of the study authors. .

Cell therapies of the future

Although the research was done on mice, it has very promising implications for human therapies. The ability to shuttle between macrophages in cell culture and their natural environment shows great potential for future macrophage-based cell therapies. Lung macrophages could be multiplied in the laboratory and experimentally adapted to fight a specific disease before being delivered to the patient’s lungs where they can immediately begin to perform their function. Such a setup could be used to treat cancer, fibrotic disease, or COVID-19-like infections in the lungs and possibly other organs.

“This study began well before the start of the pandemic but demonstrates once again that basic research can serve as a source of future therapeutic applications”, concludes Professor Sieweke.

About Professor Michael Sieweke
Professor Michael Sieweke’s research group works at the interface of immunology and stem cell research. Scientists are focusing on the study of hematopoietic stem cells and macrophages, long-lived mature cells of the immune system that play an important role in tissue regeneration. In 2018, Professor Michael Sieweke was awarded Germany’s most endowed research prize – the Alexander von Humboldt Chair, which brings top international researchers to German universities. He also received an advanced grant from the European Research Council. He is project leader at SaxoCell, a new cell therapy research cluster funded by the Clusters4Future initiative of the Federal Ministry of Education and Research (BMBF). Professor Sieweke is now Deputy Director of the Center for Regenerative Therapies at TU Dresden (CRTD).

Sethuraman Subramanian, Clara Jana-Lui Busch, Kaaweh Molawi, Laufey Geirsdottir, Julien Maurizio, Stéphanie Vargas-Aguilar, Hassiba Belahbib, Gregory Gimenez, Ridzky, Anis Advent Yuda, Michaela Burkon, Jérémy Favret, Sara Gholamhosseinian Najjar, Bérengère de Laval, Prashanth Kumar Kandalla, Sandrine Sarrazin, Lena Alexopoulou and Michael H. Sieweke: Alveolar macrophages expanded by long-term culture restore full epigenetic identity in vivoNature Immunology (February 2022)

About the Center for Regenerative Therapies Dresden (CRTD)
The Center for Regenerative Therapies Dresden (CRTD) at TU Dresden is the academic home to scientists from more than 30 countries. Their mission is to discover the principles of cell and tissue regeneration and use them for the recognition, treatment and reversal of disease. The CRTD connects the laboratory to the clinic, scientists to clinicians to pool expertise in stem cells, developmental biology, gene editing and regeneration towards innovative therapies for neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease, hematological diseases such as leukemia, metabolic diseases such as diabetes, diseases of the retina, lungs and bones.
The CRTD was founded in 2006 as a research center of the German Research Foundation (DFG) and funded until 2018 as a DFG research center, as well as a center of excellence. Since 2019, the CRTD has been funded by the TU Dresden and the Free State of Saxony.

The CRTD is one of three institutes of the central science facility Center for Molecular and Cellular Bioengineering (CMCB) at TU Dresden.

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