Cell renewal : terms and conditions may apply

by Pedro Ru

Institution: Karolinska Institute
Year: 2017
Posted: 02/01/2018
Record ID: 2155098
Full text PDF: http://hdl.handle.net/10616/45586


The longevity and turnover of the different constituent cells of an organism defineits development, size, health, and biological age. The present thesis discusses therenewal rates and functions of cells in several organs and tissues: peripheralblood, bone marrow, intestine and central nervous system. By applying a recently developed method to assess average cell age to peripheralT cell subsets, we provide evidence that in humans the thymus remains activebeyond the age of 30 and that nave T cell renewal rates slowly decreasethroughout life. We further examined how turnover rates can impact the total naveT cell population, by applying a variety of additional mathematical andcomputational models as well as functional assays. Using these approaches wepropose a model by which clonal diversity can be sustained regardless of thespatial location of the constituent cells. Furthermore, we identify a subset ofindividuals above the age of 65 who exhibit a dramatic increase in turnover despitehaving no overt pathological conditions. Given recent evidence that aging isassociated with immunological dysfunction, this observation highlights a subset ofthe population that may be more susceptible to new infections and less receptiveto vaccinations. (PAPER I). We determined that plasma cells have different renewal rates depending on thesubpopulation and, more importantly, depending on the niche. Both the bonemarrow and the intestine harbor plasma cell responders to antigens from childhoodexposures. However, bone marrow plasma cells (PAPER II) renew much fasterthan their intestinal counterparts (PAPER III). In the small intestine, some plasmacells can persist for decades without being replaced or undergoing further divisions(PAPER III). The differences described suggest different mechanisms of immunememory maintenance possibly due to different pressures in the niches. Theseresults also demonstrate that plasma cells in the bone marrow and in the intestineare 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 bodys vitalfunctions. Disturbance to cell homeostasis such as microglia depletion or spinalcord injury have tremendous consequences. Our data reveals that the vastmajority of the microglia population in the human cortex undergoes constantrenewal albeit at a slow rate. Microglia are key regulators of the CNS; theprogressive turnover of this cell population ensures the constant presence of apool of young microglia (PAPER IV). Another example of a self-sustaining cellpopulation in the CNS are ependymal cells. We showed that these resident stemcells are capable of fast proliferation and differentiation in response to spinal cordinjury. The progeny of ependymal cells play a crucial rule in scar formation helpingpreventing secondary enlargement of the wound and consequently preventingfurther deterioration. Interestingly,