Aging is caused by the time dependent accumulation of cellular damage. Such damage impairs the ability of the resident stem cell pool to renew the tissue (stem cell exhaustion), and manifests as the functional decline associated with aging. Mechanisms that increase stem cell numbers, maintenance, or function could therefore be used to counter aging related diseases.
Impact of the stem cell niche on aging
Stem cells do not exist in a void. Instead, they are surrounded, nurtured, and protected by their neighboring cells that form the stem cell microenvironment, or Niche. The Niche has also a role in informing the stem cell of the state of the tissue and organismal physiology. We have previously discovered that intestinal stem cells do not for example directly sense the nutritional state, but they rely on paracrine messages from the Paneth cells of the niche for that information. In response to low nutrient availability, stem cells are informed by the Paneth cells to concentrate on self-renewal, that is, on generation of new stem cells at the expense of reduced generation of differentiating cells. While this mechanism reduces the output of intestinal cells, it creates a larger stem cell pool ensuring faster response when food again becomes available.
As the niche has such a dramatic capacity to alter stem cell behavior and tissue maintenance, defects in such dynamic interactions could have a role in stem cell exhaustion and aging. Furthermore, niche-stem cell interactions may provide new means to manipulate regeneration.
We develop novel strategies to study the communication between stem cells and their niche. Our goal is to understand how niche-stem cell interactions are changed during aging, and if they can be manipulated. We use stem cell systems of the intestine and mammaryglands as our models both in vitro and in vivo.
Intestinal stem cells reside in the crypts together with Paneth cells. We use FACS-sorting to isolate primary stem cells and their Paneth cell niche, and can adress their separate roles in tissue regeneration and aging by their capacity to induce the formation 3-dimensional intestinal organoids in co-culture.
How do stem cell systems organize themselves for the best of the tissue
Intestinal stem cell system is a well characterized and an excellent model to study the niche and stem cell interactions. Interestingly, many cells in the intestinal niche possess great de- and transdifferentiation potential, and can follow local cues to restore tissue organization if certain cell types are lost.
Current focus of the project is to characterize the driving forces behind the self-organizing trait of stem cell niches. In addition, we are interested to study the plasticity of different cell populations within the niche. This is done in vitro with primary cell culture assays and time-lapse imaging. We are also developing in silico models for the niche interactions where we can integrate our experimental findings and test new hypotheses.
Asymmetric apportioning of damaged cellular components
Stem cell exhaustion is considered the ultimate culprit of the aging phenotype. Therefore, it is conceivable that stem cells would have evolved specific mechanisms to minimize damage accumulation. One possible way for reducing damage is to asymmetrically apportion harmful factors in cell division to the replaceable differentiating daughter, thereby reducing their content in the stem cell. Mammalian cells harbor multiple compartments with distinct composition and function. In a conceivable case, organelles within a cell form a heterogeneous pool containing old organelles with accumulated damage and reduced function, and newly made fully functional organelles. In order to secure the future of the tissue, stem cells may sort the young ‘high quality’ organelles to the stem-cell-to-be daughter, while depositing older damaged material to the daughter cell that will become a dispensable differentiating cell. We are pioneering the research on the age dependent apportioning of organelles and cellular components in mammalian stem cell division. With the tools we have developed, we can follow the age-dependent apportioning of any protein/organelle in a cell division.
(a) We use lentiviral targeting of organnelles in human mammary stem cells, and follow their age-dependent asymmetry in stem cell division by microscopy and FACS, (b) An example of a subcellular compartment that is asymmetrically inherited. P2 is the new stem cell.