The role of migration in mutant evolution in fragmented populations

Mutant evolution in fragmented populations has been studied extensively in evolutionary biology. With an increased focus on evolutionary dynamics in medical research, quantification of mutant load in fragmented populations with varying levels of migration has become especially important. Examples of fragmented populations are hematopoietic stem cell niches in the bone marrow where cells can re-circulate between niches through the blood, or colonic crypts where movement of cells across different crypts is not thought to be common. Here we use a combination of experiments and theory to investigate the role of migration in mutant distribution. In the case of neutral mutants, the experiments confirmed that while the mean number of mutants is not influenced by migration, the probability distribution is, which manifested itself in a change in the skewedness of the distribution of the mutant numbers in the demes. In the case of disadvantageous mutants, we investigated the phenomenon of the increase in the expected number of mutants compared to that of the selection-mutation balance. In a single deme, this increase is observed when the deme size is lower than the critical size, $N_c$. In a fragmented system that consists of connected demes with a probability of migration, the increase in mutant numbers above the selection-mutation balance can be maintained in small ($N<N_c$) demes as long as the migration rate is sufficiently small. The migration rate above which the mutants approach the selection-mutation balance decays exponentially with $N/N_c$. These findings are relevant in the context of the complex and poorly understood processes that may lead to changes in the clonal composition in tissues and tumors.

Hemmule: A Novel Structure with the Properties of the Stem Cell Niche

Stem cells are nurtured and regulated by a specialized microenvironment known as stem cell niche. While the functions of the niches are well defined, their structure and location remain unclear. We have identified, in rat bone marrow, the seat of hematopoietic stem cells—extensively vascularized node-like compartments that fit the requirements for stem cell niche and that we called hemmules. Hemmules are round or oval structures of about one millimeter in diameter that are surrounded by a fine capsule, have afferent and efferent vessels, are filled with the extracellular matrix and mesenchymal, hematopoietic, endothelial stem cells, and contain cells of the megakaryocyte family, which are known for homeostatic quiescence and contribution to the bone marrow environment. We propose that hemmules are the long sought hematopoietic stem cell niches and that they are prototypical of stem cell niches in other organs.

Hemmule: A Novel Structure with the Properties of the Stem Cell Niche

Stem cells are nurtured and regulated by a specialized microenvironment known as stem cell niche. While the functions of the niches are well defined, their structure and location remain unclear. We have identified in rat bone marrow, the seat of hematopoietic stem cells, extensively vascularized node-like compartments that fit the requirements for stem cell niche and which we called hemmules. Hemmules are round or oval structures of about one millimeter in diameter that are surrounded by a fine capsule, have afferent and efferent vessels, are filled with the extracellular matrix and mesenchymal, hematopoietic, endothelial stem cells, and contain cells of the megakaryocyte family, which are known for homeostatic quiescence and contribution to the bone marrow environment. We propose that hemmules are the long sought hematopoietic stem cell niches and that they are prototypical of stem cell niches in other organs.

Glioma Stem Cell Niches in Human Glioblastoma Are Periarteriolar

Survival of primary brain tumor (glioblastoma) patients is seriously hampered by glioma stem cells (GSCs) that are distinct therapy-resistant self-replicating pluripotent cancer cells. GSCs reside in GSC niches, which are specific protective microenvironments in glioblastoma tumors. We have recently found that GSC niches are hypoxic periarteriolar, whereas in most studies, GSC niches are identified as hypoxic perivascular. The aim of this review is to critically evaluate the literature on perivascular GSC niches to establish whether these are periarteriolar, pericapillary, perivenular, and/or perilymphatic. We found six publications showing images of human glioblastoma tissue containing perivascular GSC niches without any specification of the vessel type. However, it is frequently assumed that these vessels are capillaries which are exchange vessels, whereas arterioles and venules are transport vessels. Closer inspection of the figures of these publications showed vessels that were not capillaries. Whether these vessels were arterioles or venules was difficult to determine in one case, but in the other cases, these were clearly arterioles and their perivascular niches were similar to the periarteriolar niches we have found. Therefore, we conclude that in human glioblastoma tumors, GSC niches are hypoxic periarteriolar and are structurally and functionally look-alikes of hematopoietic stem cell niches in the bone marrow.