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Biomedical subjects

M Brittan

Publications and source records attributed to M Brittan.

8 recordsLinked to original sources

Markers of adult tissue-based stem cells.

The expectation generated by the pluripotentiality of embryonic stem (ES) cells has initiated a renaissance in stem cell biology. While ES cells can be harvested in abundance and appear to be the most versatile of cells for regenerative medicine, adult stem cells also hold promise, but the identity and subsequent isolation of these comparatively rare cells remains problematic in most tissues, perhaps with the notable exception of the bone marrow. Identifying surface molecules (markers) that would aid in stem cell isolation is thus a major goal for stem cell biologists. Moreover, the characterization of normal stem cells in specific tissues may provide a dividend for the treatment of cancer. There is a growing belief that the successful treatment of neoplastic disease will require specific targeting of the cancer stem cells, cells that may well have many of the characteristics of their normal counterparts.

Adult↗

The gastrointestinal stem cell.

The longevity of adult stem cells, and their potential for vast tissue regeneration, makes them a focal point of current research and debate, with future aspirations for the use of stem cells in the treatment of a number of human pathological conditions. Due to the rapid rate of cell turnover in the gastrointestinal tract, the stem cells of this tissue are amongst the most assiduous in the body, although they remain unidentified to this day due to their immature, undifferentiated phenotype. However, our knowledge of the mechanisms regulating gastrointestinal stem cell function is evolving, with the identification of putative cellular markers and the elucidation of signalling pathways which regulate cell behaviour in the normal and neoplastic gastrointestinal tract. This review describes the fundamental properties of the gastrointestinal stem cell including: (i) their number, location and origins, (ii) their primary function of deriving gastrointestinal cell lineages and maintaining tissue homeostasis, (iii) the acquisition of gastrointestinal cell lineages from adult stem cells of extraneous tissues and the consequences of this in a therapeutic context, and (iv) the genetic and morphological phenomena surrounding neoplastic transformation in the gastrointestinal tract.

Adult↗

Recipes for adult stem cell plasticity: fusion cuisine or readymade?

A large body of evidence supports the idea that certain adult stem cells, particularly those of bone marrow origin, can engraft at alternative locations, particularly when the recipient organ is damaged. Under strong and positive selection pressure these cells will clonally expand/differentiate, making an important contribution to tissue replacement. Similarly, bone marrow derived cells can be amplified in vitro and differentiated into many types of tissue. Despite seemingly irrefutable evidence for stem cell plasticity, a veritable chorus of detractors has emerged, some doubting its very existence, motivated perhaps by more than a little self interest. The issues that have led to this situation include the inability to reproduce certain quite startling observations, and extrapolation from the behaviour of embryonic stem cells to suggest that adult bone marrow cells simply fuse with other cells and adopt their phenotype. Although these issues need resolving and, accepting that cell fusion does appear to allow reprogramming of haemopoietic cells in special circumstances, criticising this whole new field because some areas remain unclear is not good science.

Adult↗

Bone marrow derivation of pericryptal myofibroblasts in the mouse and human small intestine and colon.

BACKGROUND AND AIMS: In order to establish whether extraintestinal cells contribute to the turnover and repair of gastrointestinal tissues, we studied the colons and small intestines of female mice that had received a male bone marrow transplant, together with gastrointestinal biopsies from female patients that had developed graft versus host disease after receiving a bone marrow transplant from male donors. METHODS: Using in situ hybridisation to detect Y chromosomes and immunohistochemistry, we demonstrated that cells derived from injected bone marrow frequently engrafted into the intestine and differentiated into pericryptal myofibroblasts. RESULTS: In the human intestine, we confirmed by combining in situ hybridisation with immunostaining for smooth muscle actin that the bone marrow derived cells within the intestine exhibited a myofibroblast phenotype. In female mouse recipients of male bone marrow grafts, we observed colocalisation of Y chromosomes and clusters of newly formed marrow derived myofibroblasts. While few of these were present at seven days after bone marrow transplantation, they were numerous at 14 days, and by six weeks entire columns of pericryptal myofibroblasts could be seen running up the sides of crypts in both the small intestine and colon. These columns appeared to extend into the villi in the small intestine. Within the intestinal lamina propria, these Y chromosome positive cells were negative for the mouse macrophage marker F4/80 antigen and CD34. CONCLUSIONS: Bone marrow derived pericryptal myofibroblasts were present in the mouse intestine following irradiation and bone marrow transplant, and in the intestines of human patients suffering graft versus host disease following a bone marrow transplant. Our data indicate that bone marrow cells contribute to the regeneration of intestinal myofibroblasts and epithelium after damage, and we suggest that this could be exploited therapeutically.

Animals↗

E-cadherin in the developing mouse gonad.

Expression of the cell adhesion molecule E-cadherin in the developing mouse has been investigated by immunocytochemistry and disaggregated organ culture. The principal aims were firstly, to determine whether E-cadherin is expressed in the indifferent gonad and if so with which cell population(s) it is associated. Secondly, to investigate the pattern of expression in the mesonephros, especially in relation to ventral mesonephric tubule cells, which contribute to the somatic cell population of the gonad. Thirdly, to discover whether there are any sex differences in expression of E-cadherin in differentiating gonads. Germ cells in the indifferent gonad showed strong immunoreactivity whereas somatic cells were unstained unless their membranes were in contact with those of germ cells. Positive staining for E-cadherin was found in epithelial cells of the mesonephric duct and tubules. Staining was weak at the ventral margins of the ventral mesonephric tubules. At later stages, germ cell immunoreactivity could be correlated with stages of ovarian differentiation, being reduced or absent between germ cells at 16 days post coitum, when ovigerous cords become dissociated as a prelude to follicle formation. Stronger staining reappeared briefly at 17 days post coitum, the time of follicular cell attachment to oocytes, before waning again 2 days later. Similarly, immunoreactivity in the differentiating testis was initially restricted to the germ cell population but pre-Sertoli cells were strongly positive between 16 and 19 days post coitum. The most striking sex difference was seen in the somatic cell population, where Leydig cells of the testis became strongly positive for E-cadherin from 17 days post coitum onwards. At this time, unlike controls, dissociated cells from gonads of either sex were unable to reform their initial contacts when cultured in the presence of the antibody to E-cadherin, confirming its functional importance.

Animals↗

Intestinal stem cells.

The intestinal tract has a rapid epithelial cell turnover, which continues throughout life. The process is regulated and maintained by a population of stem cells, which give rise to all the intestinal epithelial cell lineages. Studies in both the mouse and the human show that these cells are capable of forming clonal crypt populations. Stem cells remain hard to identify, however it is thought that they reside in a 'niche' towards the base of the crypt and their activity is regulated by the paracrine secretion of growth factors and cytokines from surrounding mesenchymal cells. Stem cell division is usually asymmetric with the formation of an identical daughter stem cell and committed progenitor cells. Progenitor cells retain the ability to divide until they terminally differentiate. Occasional symmetric division produces either 2 daughter cells with stem cell loss, or 2 stem cells and eventual clone dominance. This stochastic extinction of stem cell lines with eventual dominance of one cell line is called 'niche succession'. The discovery of plasticity, the ability of stem cells to engraft into, and in some cases replace the function of damaged host tissues has generated a large amount of scientific and clinical interest: however the concept remains controversial and is still a subject of hot debate. Studies are beginning to identify the complex molecular, genetic and cellular pathways underlying stem cell function such as Wnt signalling, bone morphogenetic protein (BMP) and Notch/Delta pathways. The derangement of these pathways within stem cells plays an integral part in the development of malignancy within the intestinal tract.

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