Dr Jonathan Beauchamp

Research interests

Adult Skeletal Muscle: An Archetypal Stem Cell System

Controlled and precise movement of the human body is achieved through the coordinated action of hundreds of individual skeletal muscles that connect the different elements of the articulated skeleton. Each muscle consists of ordered bundles of multinucleated muscle fibres (myofibres) that contract in unison to generate the force required for movement. Myofibres form during development by the fusion and differentiation of hundreds of precursor cells (myoblasts) and are devoted to the production, maintenance and regulation of a complex contractile protein apparatus. As in most adult tissues, specialisation is achieved by cell differentiation which, through epigenetic modification, results in the expression of a restricted gene profile appropriate to function. However, the cost of such a high degree of structural and functional specialisation is that nuclei within the myofibres (myonuclei) cannot divide. Instead, new myonuclei required for the maintenance, growth and repair of adult muscle are derived from satellite cells, a population of tissue-specific stem cells.

The satellite cell: a tissue-specific adult stem cell

A single, quiescent satellite cell (arrowed) on the surface of a freshly isolated myofibre isolated from an adult Myf5 nlacZ/+ mouse. The preparation was immunostained for b-galactosidase (red) which is expressed by satellite cells, but not by differentiated myonuclei. DAPI staining (blue) was used to reveal all of the nuclei, including b-galactosidase-negative myonuclei within the myofibre.

Each myofibre is intimately associated with a small number of undifferentiated satellite cells that are maintained on the surface of the fibre, surrounded by a common basal lamina. Satellite cells are normally quiescent, but are activated by appropriate extrinsic signals to divide and generate progeny that differentiate into the new myonuclei required for growth and repair.

An effective adult stem cell compartment must maintain a lifelong regenerative capacity. Under normal conditions, muscle homeostasis attracts little attention. However, the catastrophic consequences of ineffective regeneration become apparent in extreme situations such as Duchenne muscular dystrophy, where the satellite cell compartment becomes overwhelmed by demands of chronic muscle loss, resulting in muscle wasting and fibrotic replacement. Muscle wasting and weakness are also features of the normal process of ageing. Interestingly, this does not result from any diminution of satellite cell potency, but is probably due to a progressive decrease in cell number and changes in the satellite cell niche.

My research is focussed on how the regenerative compartment of adult skeletal muscle sustains the capacity for effective regeneration. Specifically, I am interested in how satellite cells maintain their stem cell identity; how the stem cell pool is replenished; and the role of the satellite cell niche in regulating the stem cell phenotype.

Satellite Cell Quiescence

Maintaining adult stem cells in a state of quiescence is a potentially important mechanism for preserving effective regenerative capacity. By preventing inappropriate activation in response to transient or subthreshold extrinsic stimuli, proliferative potential is preserved and the potential accumulation of replication-associated mutations reduced. Recent studies have suggested that stem cell quiescence is not simply a lack of activity, but is an actively regulated state with its own distinct profile of gene expression. We are investigating several models of satellite cell quiescence to identify genes and pathways involved in maintaining this state and regulating the initial release into activation.

How is satellite cell quiescence maintained and activation regulated?

Under normal conditions, the satellite cell pool is quiescent, but becomes activated in response to signals resulting from damage. Although the factors and pathways involved in the differentiation of satellite cell progeny are well-characterised, little is known about the maintenance and regulation of the quiescent state.

Satellite Cell Renewal

Once the regenerative compartment has been activated, satellite cells proliferate and their progeny eventually differentiate to provide new myonuclei. In order to maintain regenerative capacity, there must be a mechanism by which the satellite cell pool is replenished. Although recent studies have clearly demonstrated that satellite cells are capable of self-renewal, the mechanism(s) that regulate the balance between the loss of cells to differentiation and replenishment of the stem cell pool remain unknown. We are interested in the roles that different Notch signalling pathway components play in the behaviour of and cell fate decisions made by satellite cells and their progeny.

What regulates the fate of satellite cells and their progeny following activation?

Activated satellite cells proliferate and their progeny either (i) differentiate to provide new myonuclei for growth or repair or (ii) withdraw from the cell cycle and return to a state of quiescence. What determines this fate choice remains unknown, but the balance between differentiation and self-renewal is critical for maintaining an effective stem cell compartment.

The satellite cell niche

Adult stem cells are defined by the ability to both self-renew and to give rise to progeny destined for differentiation. However, it is becoming increasingly apparent that these intrinsic stem cell properties are subject to extrinsic regulation by the surrounding microenvironment or niche. In most tissues, stems cells are sequestered in an anatomically defined, stable niche (e.g. the osteoblast lining of bone marrow or the bulge region of the hair follicle) from which stem cell progeny destined for differentiation migrate. In contrast, satellite cells are distributed throughout the tissue, each maintained within a separate niche consisting of the underlying myofibre, surrounding extracellular matrix and overlying basal lamina. Furthermore, muscle degeneration and regeneration involve disruption and subsequent reestablishment of the niche. We are interested in how the loss of, or migration from, the niche effects satellite cell behaviour and more importantly, whether the formation of a new niche is involved in the recruitment of new satellite cells during regeneration.

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