The case for a metabolic stem cell niche. 
Despite more than 40 years of experience with the use of haematopoietic stem cells (HSC) in the clinic and the identification of a plethora of regulatory signals of clear relevance to their function, it has proven remarkably difficult to amplify these cells efficiently in culture without a concurrent loss of potential.  Based on considerations of haematopoietic environments in the embryo and the adult, on published observations of metabolic compartmentalisation between neighbouring cells in other tissues, and on considerations of the selective pressures acting on the evolution of generative and regenerative systems, we propose that the amplification of HSC may be tied obligatorily to limiting metabolic conditions provided by the niche.  We suggest that this conceptually simple arrangement could combine the support of HSC with the containment of self-renewal activity within a rare and highly defined set of physiological sites, whilst avoiding the accumulation of potentially leukaemogenic mutations in the stem cell pool.