The TAZ protein protects against age-related loss of function

by Kerstin Wagner, Leibniz Institute for Aging Research – Fritz Lippmann Institute eV (FLI)

Hematopoietic stem cells age very heterogeneously. The protein TAZ, a co-activator of the Hippo signaling pathway, can protect blood stem cells from aging. Thus, in addition to old cells, “young” cells are also detected when the protection has worked. Credit: FLI / Bjorn von Eise

A well-functioning immune system is essential for protection against infections. However, as we age, immune system function declines, also due to age-related damage to hematopoietic (blood) stem cells. Researchers at the Leibniz Institute on Aging – Fritz Lippmann Institute (FLI) in Jena, Germany, have now discovered how the co-activator of the Hippo signaling pathway, the protein TAZ, can protect hematopoietic stem cells from senescence and thus prevent them from loss of function. Furthermore, hematopoietic stem cells age very heterogeneously. In addition to old cells, “young” cells can also be found when the defense mechanism has worked effectively.

Our blood is constantly regenerated by hematopoietic stem cells (HSC). As we age, however, these blood stem cells lose function and their regenerative potential declines. In older people, there is another problem with blood formation (hematopoiesis): they make fewer lymphocytes (cells of the immune system), so they often cannot deal with infections as well and usually do not show a highly effective immune response after vaccination.

There are now numerous indications that these age-related deficiencies result primarily from age-related damage to blood stem cells. It is not yet known how this damage occurs and whether there are protective mechanisms that could protect blood stem cells from it. In a study recently published in Nature Communications, researchers from the Leibniz Institute for Aging—Fritz Lippmann Institute (FLI) and the University Hospital of Jena in Jena, Germany; Harvard University in Cambridge, Massachusetts; and ERIBA in Groningen, the Netherlands, have now used new analytical methods at the single-cell level to investigate in more detail what happens during the aging process in hematopoietic stem cells and what role the TAZ protein plays in this process.

The Hippo signaling pathway makes cells happy again

The adult body replaces billions of cells every day; in this process, existing cells are continuously replaced by “new” cells. “Maintaining the balance between cell division, cell differentiation and cell death is extremely important because even the smallest imbalances disrupt this balance and sooner or later contribute to the development of cancer or can lead to premature aging,” explains Dr. Björn von Eise, head of the Transcriptional Control of Tissue Homeostasis research group at FLI.

The Hippo signaling pathway plays a central role in tissue regeneration but also in cancer development. It controls the division of cells in organs and tissues and ensures that they acquire and maintain the correct size and shape. “The Hippo signaling pathway protects cells in the body. It’s like it makes them happy again when they’re under cellular stress,” adds Dr. von Eys. “Many genes in the Hippo signaling pathway are also upregulated in old age, but so far little is known about the role these processes play in aging.”

YAP/TAZ activity is important for tissue regeneration

The Hippo signaling pathway inhibits the activity of proteins such as YAP (Yes-associated protein) and TAZ (transcriptional co-activator with PDZ-binding motif). These are proteins that control the copying of certain DNA genes into messenger RNA (mRNA) – a process called transcription. Recent studies have shown that YAP and TAZ are also essential for tissue regeneration in the gut or liver, helping cells to better cope with the stress of tissue damage by reprogramming them to a more primitive state.

“Given their important role in regeneration, we analyzed gene expression in hematopoietic stem cells of young and old mice and tested which genes are up- or down-regulated with aging,” reports KyungMok Kim, PhD student in the lab of Dr. Björn von Eyss. “We found that genes in cells change with aging. In the cells of old mice, the TAZ protein was more strongly induced as a co-activator of the Hippo pathway, and several hundred genes were up-regulated.” The most notable aging-related change occurred in the Clca3a1 gene, so the researchers used this TAZ-induced gene as a sensitive marker for their further studies.

Interestingly, the CLCA3A1 gene product is a protein that is found on the surface of cells and is induced by the TAZ protein. Using antibodies against CLCA3A1, von Eyss’ research group was able to identify a specific population of cells expressing high or low levels of CLCA3A1. By using special single-cell methods, such as single-cell RNA-Seq or single-cell ATAC-Seq, at the Sequencing Institute’s Core Facility, it was also possible to trace the activity of TAZ in each individual cell at the cellular level and to observe it directly in vivo.

Blood stem cells age heterogeneously

In doing so, the researchers found that blood stem cells do not age uniformly. Rather, they are very heterogeneous and show admixed populations. In this way, it was possible to isolate subpopulations of old mice in which the cells were predominantly old, but also populations in which the cells were in a “youthful” state. The gene expression pattern of these cells also tends to resemble that of young hematopoietic stem cells. This is an indication that TAZ can to some extent counteract the gradual loss of stem cell function and protect blood stem cells by rejuvenating them. Therefore, genetic down-regulation of TAZ in old HSCs resulted in a drastic failure to restore the hematopoietic system upon transplantation of these HSCs.

Possibilities for stem cell rejuvenation?

“Our new findings reveal completely new perspectives on making stem cells healthy again,” says KyungMok Kim, summarizing the research findings. “On the one hand, if we can selectively filter the old from the younger blood stem cells and isolate them from the body, we could use them to stimulate the immune system and make it significantly more active again.” This approach for stem cell rejuvenation will be studied in more detail in a subsequent project.

“On the other hand, the results can help us better understand why we age so differently and why there are differences between biological and chronological age,” adds Dr. Björn von Eys. Although chronologically all cells are the same age, they still age differently.

However, if the epigenetic clock does not tick in the same way in all cells of the body, this could explain the resulting differences in the biological age of cells. Epigenetics describes chemical markers in the genome that do not affect the sequence of DNA building blocks, but determine how and which genes are read. This type of information is also transmitted when cells divide and change with aging. Cellular heterogeneity—as shown in this study in hematopoietic stem cells—could potentially result from different epigenetic markers in subpopulations. A functional understanding of these markers in hematopoietic stem cells could thus provide clues to the aging process and the diseases associated with it.

Pre-programmed aging: Gene-controlled growth in youth drives aging of blood stem cells in late life

More info:
Kyung Mok Kim et al, Taz protects hematopoietic stem cells from aging-dependent decline in PU.1 activity, Nature Communications (2022). DOI: 10.1038/s41467-022-32970-1

Provided by the Leibniz Institute for Aging Research – Fritz Lipmann Institute eV (FLI)

Quote: Blood stem cell fitness program: TAZ protein protects against age-related loss of function (2022, October 10) Retrieved October 10, 2022, from stem-cells-taz-protein.html

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