A life-time of hematopoietic cell function: ascent, stability, and decline.

Aging is a set of complex processes that occur temporally and continuously. It is generally a unidirectional progression of cellular and molecular changes occurring during the life stages of cells, tissues and ultimately the whole organism. In vertebrate organisms, this begins at conception from the first steps in blastocyst formation, gastrulation, germ layer differentiation, and organogenesis to a continuum of embryonic, fetal, adolescent, adult, and geriatric stages. Tales of the "fountain of youth" and songs of being "forever young" are dominant ideas informing us that growing old is something science should strive to counteract. Here, we discuss the normal life stages of the blood system, particularly the historical recognition of its importance in the early growth stages of vertebrates, and what this means with respect to progressive gain and loss of hematopoietic function in the adult.

De novo hematopoietic (stem) cell generation - A differentiation or stochastic process?

The hematopoietic system is one of the earliest tissues to develop. De novo generation of hematopoietic progenitor and stem cells occurs through a transdifferentiation of (hemogenic) endothelial cells to hematopoietic identity, resulting in the formation of intra-aortic hematopoietic cluster (IAHC) cells. Heterogeneity of IAHC cell phenotypes and functions has stymied the field in its search for the transcriptional program of emerging hematopoietic stem cells (HSCs), given that an individual IAHC cannot be simultaneously examined for function and transcriptome. Several models could account for this heterogeneity, including a novel model suggesting that the transcriptomes of individual emerging IAHC cells are in an unstable/metastable state, with pivotal hematopoietic transcription factors expressed dynamically due to transcriptional pulsing and combinatorial activities. The question remains - how is functional hematopoietic cell fate established - is the process stochastic? This article touches upon these important issues, which may be relevant to the field's inability to make HSCs ex vivo.

Cell Adhesiveness Serves as a Biophysical Marker for Metastatic Potential.

Tumors are heterogeneous and composed of cells with different dissemination abilities. Despite significant effort, there is no universal biological marker that serves as a metric for metastatic potential of solid tumors. Common to disseminating cells from such tumors, however, is the need to modulate their adhesion as they detach from the tumor and migrate through stroma to intravasate. Adhesion strength is heterogeneous even among cancer cells within a given population, and using a parallel plate flow chamber, we separated and sorted these populations into weakly and strongly adherent groups; when cultured under stromal conditions, this adhesion phenotype was stable over multiple days, sorting cycles, and common across all epithelial tumor lines investigated. Weakly adherent cells displayed increased migration in both two-dimensional and three-dimensional migration assays; this was maintained for several days in culture. Subpopulations did not show differences in expression of proteins involved in the focal adhesion complex but did exhibit intrinsic focal adhesion assembly as well as contractile differences that resulted from differential expression of genes involved in microtubules, cytoskeleton linkages, and motor activity. In human breast tumors, expression of genes associated with the weakly adherent population resulted in worse progression-free and disease-free intervals. These data suggest that adhesion strength could potentially serve as a stable marker for migration and metastatic potential within a given tumor population and that the fraction of weakly adherent cells present within a tumor could act as a physical marker for metastatic potential. SIGNIFICANCE: Cancer cells exhibit heterogeneity in adhesivity, which can be used to predict metastatic potential.