13 October 2022

Rejuvenating hematopoietic protein

Blood cells are constantly regenerating from hematopoietic (hematopoietic) stem cells. However, with age, these cells lose their function, and their regenerative potential decreases. Older people have another problem with hematopoiesis: fewer lymphocytes are formed, so they are often no longer able to cope with infections as well and usually do not demonstrate a highly effective immune response after vaccination.

There is already ample evidence that these aging-related deficiencies are mainly the result of age-related changes in hematopoietic cells. How this happens and whether there are mechanisms that could protect blood stem cells from it is still unknown. Researchers from the Leibniz Institute of Aging – Fritz Lipmann Institute, Germany, the University Hospital of Jena, Germany, Harvard University, USA, and the European Research Institute of Aging Biology (ERIBA), the Netherlands, used new analytical methods at the level of individual cells to study in more detail what happens during the aging process in hematopoietic stem cells cells and what role the TAZ protein plays in this process.


HIPPO Signal Path

The adult human body generates billions of cells every day, and aged cells are constantly replaced by young ones. Maintaining a balance between cell division, differentiation and death is extremely important, because even the slightest violation of this balance either contributes to the development of cancer or leads to premature aging.

The Hippo signaling pathway plays a central role in tissue regeneration, as well as in the development of cancer. It inhibits cell division in organs and tissues and controls that they acquire and maintain the correct size and shape. Many genes in the Hippo signaling pathway are also active in old age, there is insufficient information about the role these processes play in aging.

The activity of YAP and TAZ is important for tissue regeneration

The Hippo signaling pathway inhibits the activity of YAP (Yes-bound protein) and TAZ (transcriptional coactivator with PDZ-binding motif) proteins. These proteins control the transcription of certain DNA genes into matrix RNA (mRNA). Recent studies have shown that YAP and TAZ are necessary for regeneration in the intestine and liver, helping cells better cope with stress from tissue damage, reprogramming them into a more primitive state.

The researchers analyzed gene expression in the hematopoietic cells of young and old mice and checked which genes are activated or suppressed with age. They found that in the cells of old mice, the TAZ protein is much more strongly associated with the Hippo signaling pathway, and several hundred genes associated with it were activated. The most notable changes associated with aging occurred in the TAZ-induced CLCA3A1 gene, so the researchers identified it as a sensitive marker for their next studies.

The CLCA3A1 gene encodes a protein of the same name, which is located on the cell surface and is induced by the TAZ protein. Using antibodies against CLCA3A1, the research team was able to identify a specific population of cells expressing high or low levels of CLCA3A1. RNA sequencing made it possible to track the activity of TAZ in each individual cell and control it directly in vivo.

Blood stem cells age heterogeneously

Thus, blood stem cells age unevenly. Most likely, they are heterogeneous and contain mixed populations. The researchers were able to identify subpopulations in old mice in which the cells were predominantly old, and subpopulations in which the cells were in a "young" state. The gene expression of these cells also had similarities with the expression of hematopoietic stem cells of young mice. This indicates that TAZ can to some extent counteract the gradual loss of stem cell function, rejuvenating them in this way. Consequently, genetic suppression of TAZ in hematopoietic stem cells of old mice leads to a sharp inability to restore the blood system after transplantation of these cells.

Is it possible to rejuvenate stem cells?

The study helps to better understand why people age so differently and why there are differences between biological and chronological age. If scientists can selectively select and isolate old blood stem cells, it will be possible to use young cells to stimulate the immune system and make it more active again. This approach to stem cell rejuvenation will be studied in more detail in the next project of the group.

Chronologically, all cells have the same age, but they age differently. Epigenetics describes chemical markers in the genome that do not affect the sequence of nucleotides in DNA, but determine how and which genes are read. Cell heterogeneity, as shown in this study, could potentially be the result of different epigenetic markers in subpopulations. A functional understanding of these markers can explain the aging process and related diseases.

Article by K.M.Kim et al. Taz protects hematopoietic stem cells from an aging-dependent decline in PU.1 activity published in the journal Nature Communications.

Aminat Adzhieva, portal "Eternal Youth" http://vechnayamolodost.ru based on the materials of the Leibniz Institute on Aging – Fritz Lipmann Institute: Fitness program for blood stem cells: TAZ protein protects from age-related loss of function.

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