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February 16, 2015

iPS cell-derived pancreatic cells can survive and function in mice

One cause of diabetes is insufficient secretion of insulin from β-cells. Researchers have therefore investigated ways to increase and sustain the number of β-cells in the body, which is why the transplantation of progenitor cells is receiving strong consideration. One challenge in the field is protocols that culture such progenitor cells which in turn generate functional β-cells in the body. The Osafune group has discovered that the physical dimensions of the culture has significant impact on the likelihood ESCs and iPSCs will differentiate into pancreatic bud cells, which are the earliest cells committed to the pancreatic lineage. Moreover, they show transplantation of these cells into mice results in insulin-secreting β-cells.

The intention to experiment with the dimensions of the culture came from observing that in monolayer culture bud cells aggregated in a manner that resembled pancreatic budding in mouse embryos. Professor Kenji Osafune describes this observation as, "Surprising but reasonable. The pancreatic bud emerges from a primitive gut tube, which is a monolayer". To investigate whether this aggregation facilitated molecular signaling for proper differentiation, the bud cells were harvested in monolayer or aggregation cultures. After examining several human iPSC lines, the authors found that aggregation culture increased the number of bud cells, in some cases several times more. 

To become bud cells, the iPSCs needed to pass through a series of intermediates. The bud cell stage was highlighted by cells bifurcating into two: those taking the pancreatic lineage and those dying off. In other words, it appears the aggregation culture somehow selected for cells that took the pancreatic lineage. Upon transplantation into mice, a number of markers indicated that the aggregate culture bud cells differentiated into functional β-cells. "This is the most important finding," says Osafune, "that transplanted iPS cell-derived pancreatic cells can survive in mice."

The outcome of this study provokes a number of questions, as it only demonstrates the benefits of the physical environment on differentiating stem cells to the pancreatic lineage, but not on the effects of the molecular network. 
Osafune is not sure what contribution the dimension made, but does have his thoughts. "It seems cell contact-mediated signals via extracellular matrices and adhesion molecules and other membrane-bound receptors are important".

Pancreatic bud cells (green) formed tubular structures post implantation into mice.


Toyoda et al. (2015) Cell aggregation optimizes the differentiation of human ESCs and iPSCs into pancreatic bud-like progenitor cells. Stem Cell Research 14:185.

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