Cell renewal : terms and conditions may apply

The longevity and turnover of the different constituent cells of an organism define its development, size, health, and biological age. The present thesis discusses the renewal rates and functions of cells in several organs and tissues: peripheral blood, bone marrow, intestine and central nervous system. By applying a recently developed method to assess average cell age to peripheral T cell subsets, we provide evidence that in humans the thymus remains active beyond the age of 30 and that naïve T cell renewal rates slowly decrease throughout life. We further examined how turnover rates can impact the total naïve T cell population, by applying a variety of additional mathematical and computational models as well as functional assays. Using these approaches we propose a model by which clonal diversity can be sustained regardless of the spatial location of the constituent cells. Furthermore, we identify a subset of individuals above the age of 65 who exhibit a dramatic increase in turnover despite having no overt pathological conditions. Given recent evidence that aging is associated with immunological dysfunction, this observation highlights a subset of the population that may be more susceptible to new infections and less receptive to vaccinations. (PAPER I).

We determined that plasma cells have different renewal rates depending on the subpopulation and, more importantly, depending on the niche. Both the bone marrow and the intestine harbor plasma cell responders to antigens from childhood exposures. However, bone marrow plasma cells (PAPER II) renew much faster than their intestinal counterparts (PAPER III). In the small intestine, some plasma cells can persist for decades without being replaced or undergoing further divisions (PAPER III). The differences described suggest different mechanisms of immune memory maintenance possibly due to different pressures in the niches. These results also demonstrate that plasma cells in the bone marrow and in the intestine are likely to be differentially impacted by treatments that target fast renewing cells (PAPER II and III).

In mammals, the central nervous system (CNS) governs many of the body’s vital functions. Disturbance to cell homeostasis such as microglia depletion or spinal cord injury have tremendous consequences. Our data reveals that the vast majority of the microglia population in the human cortex undergoes constant renewal albeit at a slow rate. Microglia are key regulators of the CNS; the progressive turnover of this cell population ensures the constant presence of a pool of young microglia (PAPER IV). Another example of a self-sustaining cell population in the CNS are ependymal cells. We showed that these resident stem cells are capable of fast proliferation and differentiation in response to spinal cord injury. The progeny of ependymal cells play a crucial rule in scar formation helping preventing secondary enlargement of the wound and consequently preventing further deterioration. Interestingly, ependymal cells are incapable of responding to injury and originate progeny if cell division is blocked, demonstrating how the processes of cell-renewal and differentiation can be interconnected (PAPER V).

List of scientific papers

I. Pedro Réu, Jeff E. Mold, Axel Olin, Samuel Bernard, Jakob Michaëlsson, Azadeh Khosravi, Mehran Salehpour, Göran Possnert, Petter Brodin and Jonas Frisén. Dynamics of naïve T cell homeostasis in adult humans. [Manuscript]

II. Jeff E. Mold, Pedro Réu, Carl Jorns, Paola Martinez Murillo, Ann-Christin Croon, Maria Söderström, Øystein Jynge, Mehran Salehpour, Göran Possnert, Gunilla Karlsson Hedestam and Jonas Frisén. Continuous renewal of plasma cells in the human bone marrow. [Manuscript]

III. Ole J. B. Landsverk, Omri Snir, Raquel Bartolomé Casado, Lisa Richter, Jeff E. Mold, Pedro Réu, Rune Horneland, Vemund Paulsen, Sheraz Yaqub, Einar Martin Aandahl, Ole M. Øyen, Hildur Sif Thorarensen, Mehran Salehpour, Göran Possnert, Jonas Frisén, Ludvig M. Sollid, Espen S. Baekkevold and Frode L. Jahnsen. Antibody secreting plasma cells persist for decades in the human intestine. J Exp Med. 2017 Feb;214(2):309-317.
https://doi.org/10.1084/jem.20161590

IV. Pedro Réu, Azadeh Khosravi, Samuel Bernard, Jeff E. Mold, Mehran Salehpour, Kanar Alkass, Shira Perl, John Tisdale, Göran Possnert, Henrik Druid and Jonas Frisén. The lifespan and turnover of microglia in the human brain. [Manuscript]

V. Hanna Sabelström, Moa Stenudd, Pedro Réu, David O. Dias, Marta Elfineh, Sofia Zdunek, Peter Damberg, Christian Göritz, Jonas Frisén. Resident neural stem cells restrict tissue damage and neuronal loss after spinal cord injury in mice. Science. 2013 Nov 1;342(6158):637-40.
https://doi.org/10.1126/science.1242576