Stem cells

Chapter 8
Stem cells

Although all cells in the adult mammalian body derive from the zygote, there are many intermediate steps which contribute to the complex process of tissue and organ development. Cells which derive from the inner cell mass, referred to as embryonic stem cells, form the basis of the structures and body systems necessary for the formation of a defined pattern of growth during embryological and foetal stages of development. The characteristics of stem cells which set them apart from other cells in the adult mammalian body include their ability to retain an undifferentiated state and also to undergo self‐renewal, producing identical daughter cells which retain these same characteristics (Table 8.1). The zygote is totipotent and has the ability to develop into an embryo including its foetal membranes. In the early embryo, totipotent cells differentiate, eventually producing cells with increasingly specialised functions. The term ‘differentiation’ describes a progressive process whereby cells and tissues develop specific structural and functional roles characterised by their specialised physiological or biochemical activities. This process is preceded by ‘commitment’ to a particular cell fate where the cell may not appear morphologically differentiated but its developmental fate is determined. The term ‘committed’ stem cell is also used to describe cells which have undergone differentiation but are restricted in terms of the cell lineage into which they can develop. This stage is followed by a labile phase termed ‘specification’ where the cell is capable of differentiating without further stimuli. At this stage, however, cell commitment is capable of being reversed. This is followed by ‘determination’, a stage at which the fate of the cell cannot normally be reversed, irrespective of external signalling. Stem cell nomenclature relates to the characteristics and origin of the cells being described. Accordingly, the terms ‘embryonic stem cells’ and ‘adult stem cells’ are applied to those cells which derive from the inner cell mass of the mammalian blastocyst in the former and those present in mature tissues or organs in the latter. Pluripotent stem cells are those which can develop into all the cell types of the embryo with the exception of the trophoblastic cells. The term ‘multipotent’ is used to describe stem cells which have the capacity to develop into limited subsets of cell types, such as white blood cells or epithelial cells. In contrast, unipotent stem cells are restricted to a single differentiation pathway. ‘Progenitor cells’ belong to a category of cells related to stem cells, but have a limited self‐renewal capability, are usually more differentiated than stem cells and have the ability to divide a limited number of times before differentiating into definitive cell types.

Table 8.1 Categories and characteristics of mammalian stem cells.

Stem cell type Origin / Characteristics Competence Comments
Totipotent stem cells Inner cell mass in developing embryo Have the ability to form every cell type present in the embryo including trophoblastic placental cells The totipotency of embryonic stem cells is retained by cells of the inner cell mass for a limited number of cell divisions
Pluripotent stem cells Embryonic cells Have the ability to form all embryonic cell types except trophoblastic placental cells Pluripotent stem cells have the ability to produce viable embryos
Induced pluripotent stem cells Somatic cells reprogrammed by:
introduction of transcription factors which induce nuclear reprogramming in fully differentiated cells from an adult mammal; somatic cell nuclear transfer into an enucleated oocyte. Additional methods for induction of pluripotent stem cells include in vitro culture of primordial germ cells and culture of spermatogonial stem cells
These induced pluripotent stem cells have similar characteristics to naturally formed pluripotent stem cells These induced cells can give rise to viable embryos
Multipotent stem cells These embryonic cells have the ability to generate a limited range of subsets of cell types Multipotent stem cells are restricted in their lineage capabilities Subsets of cells produced are limited to defined cell types such as epithelial cells or white blood cells
Committed stem cells These cells are more differentiated than multipotent stem cells Committed stem cells have limited lineage capabilities Cells produced are confined to a narrower range of cell types than those produced by multipotent stem cells
Progenitor cells Although grouped with stem cells, these particular cells have limited self‐renewal capabilities Because they are more differentiated than stem cells, their self‐renewal capability is limited These cells give rise to a limited range of cell types
Unipotent stem cells Unlike progenitor cells, these cells are restricted in their ability to divide Unipotent stem cells are destined to become definitive cell types after a limited number of divisions Because these cell are more differentiated than other types of stem cells, they become definitive cell types after limited differentiation

Stem cells in the embryo

During embryonic development, stem cells of numerous lineages play a central role in the formation of body structures. The cells which arise from the blastocyst progressively differentiate into the three germ layers, endoderm, ectoderm and mesoderm, an initial step toward specialisation from which the tissues and organs of the body are formed. As it is now feasible to produce the three germ layers from embryonic stem cells with appropriate paracrine factors and culture conditions in vitro, a clearer understanding of the events leading to the formation of the three germ layers is beginning to emerge (Fig 8.1).

Image described by caption and surrounding text.

Figure 8.1 Outline of the growth and differentiation of pluripotent stem cells derived from the fertilised oocyte or alternatively by transfection of adult somatic cells.

There is much interest in the molecular mechanisms that take place during early embryonic lineage specification. New technologies such as RNA sequencing and whole genome bisulphite sequencing are enabling scientists to examine at high resolution the transcriptome and the epigenome, respectively. These data enable scientists to examine holistically the subtle molecular changes that take place in advance of the expression of lineage‐specific surface markers. There is evidence that during germ layer development cells undergo epigenetic priming prior to detectable changes in gene expression, where specific transcription factors such as Foxa‐2 modulate histone modifications which subsequently alter the transcriptome of these cells, directing them along a defined developmental trajectory.

Stem cells in adult mammals

In adult mammals, many organs and tissues contain stem cells, enabling their self‐renewal and repair. Stem cells ensure the orderly replacement of cells with defined life spans such as red blood cells and epithelial cells and, in addition, replacement of cells which are damaged by trauma, infectious diseases or other degenerative changes associated with ageing. The ability of a cell to survive and function as a stem cell is strongly influenced by the microenvironment in which the cell resides. The term stem cell niche describes those microenvironments in which these specialised cells can reside, undergo self‐renewal and proliferate without differentiating. Niches may be composed of cells alone, or cells in association with extracellular matrix (ECM) which can act as a source of secreted or cell surface factors including members of the Notch, Wnt, Fgf, Egf, Tgf‐β, stem cell factor (Scf) and chemokine families, thereby controlling stem cell renewal, maintenance and survival. Three reasons for a special environment for these cells are proposed: (1) stem cells require special support to ensure viability, (2) the growth factors and cell surface molecules produced by niche cells may collectively control stem cell pools and (3) niches function to coordinate different cell types within tissue compartments.

The bone marrow is a typical example of a stem cell niche which supplies the appropriate conditions for self‐renewal and proliferation of haematopoietic stem cells, including stromal cells, chondrocytes and adipocytes, which maintain blood cell types and numbers throughout adult life (see Chapter 15). In addition, there are subpopulations of stem cells which supply the body’s needs through the production of lineage‐restricted cells, destined to differentiate into defined cell types such as red blood cells, lymphocytes and mast cells.

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Sep 27, 2017 | Posted by in GENERAL | Comments Off on Stem cells

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