Stem cell plasticity revisited: The continuum marrow model and phenotypic changes mediated by microvesicles

Population model of stem cell phenotype. Numbers and circles represent different phenotypic cell classes. The concept here is that the phenotypes change at different points in cell cycle and eventually return to the original phenotype. For example, cell #1 is a long-term repopulating cell in G₂/M/G₀ and becomes a different cell in G₁, a colony-forming unit megakaryocyte (CFU-Meg) in S phase, then returns to the original phenotype. In this model, the individual cell phenotype continuously changes while the population remains stable. CLP = common lymphoid progenitor; ETC = et cetera.

Marrow conversion to epithelial lung cell. This shows conversion of a marrow stem cell phenotype to a pulmonary epithelial cell, which is affected by host irradiation, treatment of host or exogenous marrow cells with granulocyte colony-stimulating factor (G-CSF) and stem cell phenotype.

Marrow-lung coculture. Marrow cells were cocultured across from lung fragments but separated from them by a cell impermeable (0.4 μm) membrane for 2 or 7 days and expression of pulmonary epithelial genes in marrow cells determined by reverse transcription polymerase chain reaction (RT-PCR) analysis.

Lung-derived microvesicles. (A−D) shows a marrow cell with incorporated PKH26 and carboxyfluorescein diacetate succinimyl ester−labeled lung-derived microvesicles. (A) merged image; (B) DAPI filter; (C) Texas Red filter; (D) fluorescein isothiocyanate filter. (E) An electron micrograph of fluorescent-activated cell sorting-sorted lung-derived microvesicles. Red bar = 10 μm; black bar = 100 nm.

Injury induction of microvesicles. Irradiation injures a nonhematopoietic cell that releases bioactive microvesicles containing protein, messenger RNA (mRNA) and microRNA. These microvesicles enter marrow cells and alter their phenotype to that of the cell of microvesicle origin.

Effect of microvesicles on the stem cell population model. This indicates that microvesicles impose a different order of phenotypic change on stem cells progressing through a cell-cycle−related stem cell continuum. CLP = common lymphoid progenitor; ETC = et cetera.

Stem cell modulogram. Stem cells progressing though cycle continuously change individual cell phenotypes while maintaining the population phenotype. This is further modulated by microvesicle cell entry and the final cell fate determined by interactions with different microenvironments.

Concepts of stem cell plasticity. Panel 1 indicates that marrow-derived microvesicles may enter lung cells and induce marrow characteristics in the lung cells. Panel 2 indicates than lung-derived microvesicles may enter marrow cells and alter their phenotype toward that of a lung cell.