The development of the embryo during pregnancy is one of the majority of complex processes in life. Genes are strongly activated, plus developmental pathways must do their job in a highly precise and precisely timed manner. So-called Hox-genes play an essential regulatory role in this process. Although remaining detectable within stem cells of adult tissues throughout life, right after birth they are only rarely active,. Now, however , experts from the Leibniz Institute on Aging — Fritz Lipmann Institute (FLI) in Jena, Germany have shown that, within old age, one of these Hox-genes (Hoxa9) is strongly re-activated within murine muscle stem cells after injury; leading to the decline in the regenerative capacity of skeletal muscle. Curiously, when this faulty gene re-activation was inhibited simply by chemical compounds, muscle regeneration was improved in aging rodents, thus suggesting novel therapeutic approaches aimed at improving muscle tissue regeneration in old age. The study is published in the medical journal Nature on Nov 30, 2016.
Service of embryonic genes in aging stem cells — a new course of stem cell and tissue aging
The biggest surprise from the current study would be that the re-activation of Hoxa9 after muscle injury in senior years impairs the functionality of muscle stem cells — rather than improving it. Dr . Stefan Tü mpel, co-corresponding writer and postdoc at the FLI, explains — “Originally, Hoxa9-induced developmental pathways are responsible for the proper development of body axes — for example , during development of the fingers of a hand. inch Dr . Julia von Maltzahn is leading the research team on muscle stem cells at the FLI. She provides that — “A decline in stem cell features leads to an unavoidable decrease in the regenerative capacity from the whole skeletal muscle. With age, this may weaken the particular muscular strength after injury. ” The courses associated with stem cell and tissue aging are yet to become completely understood. It has already been recognized that signals which usually control the development of the embryo become activated in getting older stem cells. However , the regulator-genes controlling these indicators have not yet been analyzed in aging. “From a good evolutionary perspective, Hox-genes are very old. They regulate body organ development across almost the entire animal kingdom — through flies up to humans. It is a huge surprise that the defective re-activation of these genes leads to stem cell aging within muscle. This finding will fundamentally influence our knowledge of the courses of aging, ” expects Prof. E. Lenhard Rudolph, Scientific Director at the FLI.
Altered epigenetic stress response
The activation of developmental genes in an embryo should be timed very precisely, in order to ensure faultless tissue development and organ development. This fragile process is controlled by alterations of the epigenome — i. e. chemical substance modifications of the DNA. In collaboration with Dr . Alfredia Feller and Prof. Dr . Ruedi Aebersold from ETH Zurich, a new methodological approach was applied to identify the particular epigenetic changes that occur in muscle stem tissues after injury, as putative causes for the re-activation associated with Hox-genes in old age. Simon Schwö rer is a PhD Student at the FLI and first author of the papers. He describes how, “Surprisingly, old muscle stem tissues did not show a faulty activation of the epigenome within quiescence — the resting stage in non-injured muscle tissue. Only in response to a muscle injury, do the stem cellular material display an abnormal epigenetic stress response, which leads towards the opening of DNA and, thus, to the activation associated with developmental pathways. ” Working alongside scientists from Jena und Zurich were collaborators from Ulm, Heidelberg, La and Rochester; all of whom contributed significantly to the amazing results.
Future perspectives: Regenerative medication
In collaboration with the University Medical center Jena (UKJ), Prof. K. Lenhard Rudolph plans to check into, “… whether a similar re-activation of embryonic genes can also be causative for the loss of muscle maintenance in aging human beings. ” The Nature study proves already that medical substances that limit alterations in the epigenome, may improve the regenerative capacity of muscles in old mice. Thus far, this method is too unspecific and affects the modification of genetics in several cells and tissues. For this reason, a collaborative study with the “Jena Center for Soft Matters” (Dr. Anja Trä ger) is primed to investigate whether a nanoparticle-induced, target-specific inhibited of Hox-genes in muscle stem cells is achievable and, if so, would it be sufficient to improve muscle reconstruction and maintenance.
Materials given by Leibniz Institute on Aging – Fritz Lipmann Institute (FLI) . Note: Articles may be edited for style and length.