The study was
led by Prof. Dr. Henrik Semb, Director of the Institute of Translational Stem
Cell Research, Helmoltz Zentrum München, Neuherberg,
Germany. He is also a Professor of Human Stem Cell Biology and the Executive
Director of the Novo Nordisk Foundation Center for Stem Cell Biology (DanStem)
at the University of Copenhagen, Copenhagen, Denmark.
research focuses on replacement therapies to generate insulin-producing
pancreatic β-cells from human
. So far, strategies to
engineer specialized cells from pluripotent stem cells have been largely based
on empirical approaches.
The new study
has found the signaling mechanism responsible for determining whether the
progenitor cells of the pancreas will differentiate into insulin-secreting
β-cells or duct cells. In this regard, Semb said:
Extracellular Matrix Determines
Differentiation of Progenitor Cells:
cells, like stem cells
, can undergo self-renewal and
differentiation into mature cell types. However, their capacity of self-renewal
is not as robust as that of stem cells. During organ formation, the progenitor
cells are difficult to study due to their dynamic behavior.
this difficulty, the researchers spotted these human stem cell-derived progenitor
cells onto glass slides, micropatterned with various matrix proteins. This
enabled the study of the interactions between the progenitor cells with the
different matrix proteins, without any interference from the neighboring cells,
thus simulating the real-life scenario of how the progenitor cells interact
with their surroundings.
"This enabled us to discover something very surprising. Our
investigation revealed that interactions with different extracellular matrix
components change the mechanical force state within the progenitor. These
forces result from interactions between the extracellular matrix, which is
outside the cell, and the actin cytoskeleton, which is within the cell,"
Mechanism of Mechanosignaling
The pancreas is
made up of two types of cells - endocrine and epithelial. The endocrine cells
are present in the islets of Langherans. These include the insulin-secreting
β-cells and the glucagon-secreting α-cells. On the other hand, the epithelial
cells line the walls of the ducts, which carry the pancreatic fluids,
containing the hormones and digestive enzymes, into the gut.
In the present
study, it was shown that exposure to the
extracellular matrix protein laminin
progenitor cells to differentiate into endocrine cells, due to reduced
mechanical forces within the cells. On the contrary, exposure to fibronectin
led the progenitor cells to differentiate into duct cells due to
increased mechanical forces. This is the basis of the mechanosignaling
mechanism discovered by Semb and his group.
Molecular Pathway of Mechanosignaling
pathway involved in mechanosignaling was deciphered by the lead authors Anant
Mamidi and Christy Prawiro. They showed that the extracellular matrix
proteins exploit an integrin receptor present on the cell surface to send a
signal into the cell.
This results in changes in the
mechanical forces within the cell, which are transmitted by the actin proteins
making up the cytoskeleton. These forces are sensed by an intracellular protein
called the 'Yes-associated protein (YAP)'
switches "on" or "off" specific genes.
This molecular signaling cascade is
responsible for the differentiation of the progenitor cells into either
endocrine or duct cells. This mechanosignaling pathway has been validated in vivo
to establish its physiological
relevance during the development of the pancreas.
Implications of the Study
findings will enable the replacement of many existing empirically-derived
substances whose mechanism of action in progenitor cell differentiation is
unknown, with well-defined molecular inhibitors that can specifically target
the components of the newly discovered mechanosignaling pathway.
approach will enable the cost-effective and more robust production of
insulin-producing pancreatic β-cells from human pluripotent stem cells for the
treatment of diabetes
. "Our discovery breaks new ground because it explains how
multipotent progenitor cells mature into different cell types during organ
Semb said. "It also gives us the tools to recreate the
processes in the laboratory, to more precisely engineer cells that are lost or
damaged in severe diseases, such as type-1 diabetes and neurodegenerative diseases, for
future cell replacement therapies."
- Mechanosignalling via integrins directs fate decisions of pancreatic progenitors - (http://dx.doi.org/10.1038/s41586-018-0762-2)