Research Article: Self-Renewal of Stem Cells

Date Published: July , 2009

Publisher: A.I. Gordeyev

Author(s): V.V. Terskikh, Ye.A. Vorotelyak, A.V. Vasiliev.



Asymmetric division is one of the most fundamental characteristics of adult stem cells , which ensures one daughter cell maintains stem cell status and the other daughter cell becomes committed to differentiation. New data emerged recently that allow us to conclude that asymmetric division has another important aspect: it enables self-maintenance of stem cells.

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The central aspect of stem cell biology is asymmetric division. Earlier it was suggested that with the help of asymmetric division two problems could be solved at the same time: one daughter cell preserves the qualities of the stem cell and continues to self- renew, whereas the other acquires the ability to differentiate [1. 2, 3, 4]. Stem cell niches create an asymmetric microenvironment and control local processes of proliferation and differentiation of stem cells through the integration of signals from neighbor cells, from the organism, and from the external environment [5]. Niches create a system of signals directed toward the maintenance of stem cells. That has been studied in detail on germline stem cells in Drosophila. For example, it was shown on the germinal stem cells in the Drosophila ovary how the signal from the stromal cells (Dpp) regulates the self-renewal of the stem cells and influences the fate of the daughter cells [6]. In the process of ontogenesis and during the neoplastic transformation, stem cells may divide both symmetrically and asymmetrically, depending on the circumstances under which they reside [2].

One of the most studied models of asymmetric division is neural progenitor cells (neuroblasts) of Drosophila that produce the majority of the central nervous system cells. Neuroblast undergoes asymmetric division and produces two daughter cells of different sizes. The bigger cell maintains the qualities of the neuroblast and may divide several times asymmetrically, whereas the smaller daughter cell, which is called the mother ganglion cell, is committed to differentiation and divides only once, producing two neurons or two glia cells. A large number of protein complexes take part in cell polarization [25, 26]. Apical-basal polarization of the neuroblast takes place in the late G2, when the set of proteins called Par complex localizes in the apical part of the cell. For the successful proceeding of mitosis, correct localization of the protein complexes in the apical cortex of neuroblast is needed [24]. Segregation of baso-lateral and apical protein complexes is based on their antagonism that brings about their polar distribution in the cell.

Asymmetric division in higher organisms has yet to be studied sufficiently. Sporadic findings show that such divisions take place. In many epithelial tissues, both symmetric and asymmetric cell divisions are detected. For example, during symmetric mitoses, both cells are morphologically identical and situated on the basal membrane; during asymmetric mitosis, the daughter cells are morphologically different, whereas one of them transits immediately to the epithelial suprabasal layer. It is possible to suggest that during the asymmetric and symmetric divisions different mechanisms of cell migration to the suprabasal layer can exist. In the basal cells of the human esophagus, epithelium asymmetric division has been described [37], during which mitotic spindle is oriented perpendicularly to the basal membrane, which is why one daughter cell retains contact with the basal membrane and another moves into the suprabasal layer. The authors suggest that this is how stem cells divide. In a mouse epidermis on the 12.5 d of embryonic development, the large part of epidermis consists of one layer and the overwhelming number of cell divisions take place in the epithelium plane (i.e. they are symmetric); however, some cells divide perpendicularly to the basal membrane. While multilayered epithelium appears after 15.5 d of gestation, more than 70% of the cells have vertically aligned spindle. Evidently, stratification of epidermis resulted from asymmetric mitotes [38]. In mouse tail epidermis, about 30% of the basal layer cells may undergo asymmetric division [39]. Lamprecht [40] showed that, in the basal cells of rat cornea epithelium, both symmetric and asymmetric mitoses occur.

The question of age-related changes in stem cells in the course of aging of the organism and its tissues where stem cells are localized is of crucial importance for stem cell biology [52]. In quickly renewing tissues (such as blood, epidermis, and the intestinal epithelium), stem cells make up a remarkable component and have a big proliferative potential. Mouse hematopoietic stem cells function throughout the lifetime of the animal, and serial transplantations have shown that the life expectancy of stem cells may significantly exceed the life expectancy of the organism. It was shown in many experiments that aging, as well as younger bone-marrow cells are able to restore hematopoiesis in recipients after repeated transplantations [53, 54, 55]. After several rounds of transplantation, the ability of stem cells to rescue lethally irradiated animals is lower: however, it is worth noticing that, at the same time, the proliferative potential of stem cells may not be exhausted, but unfavorable effects may be connected with the technique of isolation and transplantation of stem cells, as well as the radiation treatment of recipient niches [56, 57}. This makes it possible to suggest that, with the organism aging, no essential lowering of the proliferative potential occurs in stem cells. Naturally, then, the question arises as to whether stem cells age or not. This question cannot be unambiguously solved right now. Stem cells aging can be of a replicative character (as a result of the accumulation of errors during the repeated proliferative cycles) and of a chronological character, connected with different aspects of stem cell behavior. Though the hemopoietic stem cells (HSC) of younger and older mice were similar in their ability to restore hematopoiesis, older animals had five times more HSC than the younger ones: however, they were worse at finding niches and engrafting the bone marrow of irradiated recipirnts. HSCs of young animals were predominantly quiescent, whereas in older animals they were more often in the proliferative cycle [58, 59]. Clonal analysis of the repopulating HSCs showed that aging animals have a diminished number of lymphoid-biased HSCs, while the number of the long-term HSCs of the myeloid series rises. Myeloid HSCs of the younger and older animals behave in the same way in all aspects. This leads us to suggest that aging does not influence the qualities of individual SC, but it affects the clonal composition of the HSC. Evidently, the reduction in the level of lymphocytes in the blood may be an indicator of HSC aging [60]. Rossi et al. [61] showed that in aging animals endogenous DNA errors accumulate in stem cells; that may be the cause of cell aging and can be reflected in the SC functioning and maintenance of the tissue homeostasis during stress. Behavior of HSCs as the organism ages may also depend on the genetic factors manifested in different lines of mice. The number of HSCs in DBA line barely changes with the age of animals, and the number of young HSCs even falls, whereas both factors in older animals significantly increase in C57BL/6 line.