Periodic Reporting for period 4 - Age Asymmetry (Age-Selective Segregation of Organelles)
Período documentado: 2020-11-01 hasta 2021-04-30
Young tissues are effectively renewed and can regenerate after considerable damage. However, as we age, the function of tissue resident stem cells, so-called adult stem cells, decreases and results in reduced regenerative capacity. This slows down recovery from accidents, limits dosing of standard of care drugs such as chemotherapeutics, and will eventually result in the functional decline of all organs and in onset of most age-associated diseases. Strategies maintaining or boosting stem cell capacity of tissue stem cells could therefore have major impact by countering aging-associated vulnerabilities.
In order to undertake their tissue renewing task, stem cells must undergo cell divisions and produce daughter cells that differentiate to the functional cells of the given tissue, and daughter cells that remain as self-renewing stem cells ensuring future tissue renewal. Some stem cells divide asymmetrically to produce these two daughter cells in on division. However, what cellular material is asymmetrically apportioned in such divisions has not been systematically studied, and focus has been on quantitatively asymmetric inheritance of transcription factors. However, we discovered that mitochondria - the organelles central to the cellular metabolism - are segregated qualitatively and age-selectively between daughter cells in asymmetric cell divisions. In this project we study 1) how stem cells recognize the age of their organelles and segregate them age-selectively, 2) what other compartments besides mitochondria are age-selectively segregated, and 3) is age-selective inheritance of organelles lost during aging and can it be promoted to counter aging induced loss of stem cells.
In order to undertake their tissue renewing task, stem cells must undergo cell divisions and produce daughter cells that differentiate to the functional cells of the given tissue, and daughter cells that remain as self-renewing stem cells ensuring future tissue renewal. Some stem cells divide asymmetrically to produce these two daughter cells in on division. However, what cellular material is asymmetrically apportioned in such divisions has not been systematically studied, and focus has been on quantitatively asymmetric inheritance of transcription factors. However, we discovered that mitochondria - the organelles central to the cellular metabolism - are segregated qualitatively and age-selectively between daughter cells in asymmetric cell divisions. In this project we study 1) how stem cells recognize the age of their organelles and segregate them age-selectively, 2) what other compartments besides mitochondria are age-selectively segregated, and 3) is age-selective inheritance of organelles lost during aging and can it be promoted to counter aging induced loss of stem cells.
We have validated that certain stem cells indeed segregate mitochondria age-selectively. More importantly, by using novel techniques developed by this project, we have elucidated how old and young mitochondria differ. This has opened new avenues for us to study the mechanisms of physical segregation, but has also provided unexpected insights on the reasons why stem cells segregate their mitochondria asymmetrically. We have identified major differences between old and young mitochondria, and how their selective inheritance biases the new daughter cells immediately after cell division.
Second, by studying other cellular components, we have discovered that age-selective inheritance is not restricted to mitochondria. Interestingly, while stem cells inherit young mitochondria, they selectively enrich old subpopulation of some other organelles. We are currently analyzing how this opposing age-selective enrichment of various sub-cellular components impacts stem cell function.
Finally, we have generated mouse models that will allow us to address which tissue stem cells segregate organelles age-selective, and whether this novel phenomenon is altered during normal aging and various regenerative programs.
Second, by studying other cellular components, we have discovered that age-selective inheritance is not restricted to mitochondria. Interestingly, while stem cells inherit young mitochondria, they selectively enrich old subpopulation of some other organelles. We are currently analyzing how this opposing age-selective enrichment of various sub-cellular components impacts stem cell function.
Finally, we have generated mouse models that will allow us to address which tissue stem cells segregate organelles age-selective, and whether this novel phenomenon is altered during normal aging and various regenerative programs.
This project started on the basis of an unpublished finding and phenomenon (now published: Katajisto et al., Science 2015). We have now developed novel methods allowing, for the first time, age-selective analysis of subcellular compartments such as organelles in living tissues. Beyond the goals of this project, our approaches revealed an unexpected way cellular fate is determined after division. This fate determination is central to tissue renewal maintaining our tissues throughout life, and by the tools discovered in this project, we aim to develop strategies to promote tissue repair and recovery in the elderly.