Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Next step towards replacement therapy in type 1 diabetes

29.11.2018

Scientists have discovered the signals that determine the fate of immature cells in the pancreas. The research shows that they are very mobile and that their destiny is strongly influenced by their immediate environment. This breakthrough published in the journal ‘Nature’ will facilitate the manufacturing of pancreatic islet cells from stem cells and might help combating type 1 diabetes. Prof. Dr. Henrik Semb who led the study recently joined Helmholtz Zentrum München. Follow the link to see Henrik Semb explaining the paper in a nutshell: https://vimeo.com/303012751

Type 1 diabetes is an autoimmune disease destroying the insulin-producing beta cells in the patient’s pancreas. Current approaches for replacement therapies aim to generate insulin-producing beta cells from human pluripotent stem cells.


Image of an embryonic pancreatic bud cultured ex vivo: Treatment with YAP inhibitor Verteporfin resulted in enhanced endocrine differentiation (red and green).

© DanStem

Until now, the engineering of specialized cells from pluripotent stem cells has largely been based on empirical knowledge of what works. “We have now been able to map the signal that determines whether pancreatic progenitor cells will become endocrine, such as insulin-producing beta cells or duct cells”, says Prof. Dr. Henrik Semb.

He is the Director of the Institute ofTranslational Stem Cell Research at Helmholtz Zentrum München as well as Professor and Executive Director of the Novo Nordisk Foundation Center for Stem Cell Biology (DanStem) at the University of Copenhagen.

“The cells are analogous to pinballs, whose ultimate score is based on the sum of pin encounters. They are constantly moving around within the developing pancreas, leading to frequent environmental changes. We show that the exposure to specific extracellular matrix components determines the ultimate destiny of the cells”, Semb explains.

The matrix determines the destiny

Progenitor cells are similar to stem cells since they can both self-renew and differentiate into mature cell types. However, their self-renewal capacity is generally limited compared with that of stem cells. The dynamic behaviour of progenitors during organ formation makes them difficult to study.

To overcome this obstacle, the scientist seeded human stem cell–derived progenitors on glass slides micropatterned with different matrix proteins. Using this approach, the researchers could study how each progenitor, without the influence of neighbouring cells, reacts to its 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.”

Pancreatic endocrine cells include all hormone-producing cells, such as insulin-producing beta cells and glucagon-producing alpha cells, within the islet of Langerhans, whereas the duct cells are epithelial cells that line the ducts of the pancreas. “The experiments show that exposure to the extracellular matrix laminin instructs the progenitor cells towards an endocrine fate by reducing mechanical forces within the cells. Vice versa, exposure to fibronectin results in a duct fate because of increased mechanical forces.”

Mechanism facilitates exploitation

Through the detailed analyses by the two first authors from DanStem Drs. Anant Mamidi and Christy Prawiro the researchers then uncovered the molecular details of the respective signaling pathway* and were even able to validate the physiological relevance in vivo during pancreas development.

“We can now replace significant numbers of empirically derived substances, whose mode of action in current state-of-the-art differentiation protocols is largely unknown, with small molecule inhibitors that target specific components of the newly identified mechanosignalling pathway”, Henrik Semb explains.

With this new strategy, insulin-producing beta cells can now be more cost-effectively and robustly produced from human pluripotent stem cells for future treatments against diabetes.

“Our discovery breaks new ground because it explains how multipotent progenitor cells mature into different cell types during organ formation”, Semb says. “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.”

Further Information

* They showed that components in the extracellular matrix trigger a signal into the cell via an integrin receptor, resulting in changes in mechanical forces transmitted through the actin cytoskeleton. The yes-associated protein (YAP) then senses these forces to turn on and off specific genes. This cascade determines the ultimate fate of the progenitor cell.

“Perhaps the most astonishing achievement is that our data answer an enigma that has puzzled the field for decades”, Henrik Semb says. “How some progenitors mature into duct cells, whereas others become endocrine cells via Notch signals.” The researchers show that the seemingly stochastic regulation of Notch function is in fact mediated by the progenitor’s encounters with extracellular matrix interactions via the force-sensing gene regulator protein YAP.

Related articles:
Henrik Semb to lead new Institute of Translational Stem Cell Research
https://www.helmholtz-muenchen.de/en/press-media/press-releases/all-press-releas...
The Helmholtz Zentrum München embarks on a strategic partnership with Novo Nordisk Foundation Center for Stem Cell Biology (DanStem)
https://www.helmholtz-muenchen.de/en/press-media/press-releases/all-press-releas...

The Helmholtz Zentrum München, the German Research Center for Environmental Health, pursues the goal of developing personalized medical approaches for the prevention and therapy of major common diseases such as diabetes, allergies and lung diseases. To achieve this, it investigates the interaction of genetics, environmental factors and lifestyle. The Helmholtz Zentrum München is headquartered in Neuherberg in the north of Munich and has about 2,300 staff members. It is a member of the Helmholtz Association, a community of 18 scientific-technical and medical-biological research centers with a total of about 37,000 staff members. http://www.helmholtz-muenchen.de/en

The objective of the Institute of Translational Stem Cell Research (ITS) is to develop a stem cell-based replacement therapy in type 1 diabetes. The scientists aim to develop safe approaches for up-scaled production of insulin-producing beta cells from human pluripotent stem cells (hPSCs). An important milestone in the short term is the proper production of the cells following defined standards of Good Manufacturing Practice (GMP). To this end, the ITS works closely together with the University of Copenhagen. http://www.helmholtz-muenchen.de/its

Contact for the media:
Department of Communication, Helmholtz Zentrum München - German Research Center for Environmental Health, Ingolstädter Landstr. 1, 85764 Neuherberg - Tel. +49 89 3187 2238 - E-mail: presse@helmholtz-muenchen.de

Wissenschaftliche Ansprechpartner:

Prof. Dr. Tor Henrik Semb, Helmholtz Zentrum München - German Research Center for Environmental Health, Institute of Translational Stem Cell Research, Ingolstädter Landstr. 1, 85764 Neuherberg - Tel. +49 89 3187-49133 – E-mail: henrik.semb@helmholtz-muenchen.de

Originalpublikation:

Mamidi, A. & Prawiro, C. et al. (2018): Mechanosignalling via integrins directs fate decisions of pancreatic progenitors. Nature, DOI: 10.1038/s41586-018-0762-2

Weitere Informationen:

https://vimeo.com/303012751

Sonja Opitz | Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt

More articles from Life Sciences:

nachricht New eDNA technology used to quickly assess coral reefs
18.04.2019 | University of Hawaii at Manoa

nachricht New automated biological-sample analysis systems to accelerate disease detection
18.04.2019 | Polytechnique Montréal

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Explosion on Jupiter-sized star 10 times more powerful than ever seen on our sun

A stellar flare 10 times more powerful than anything seen on our sun has burst from an ultracool star almost the same size as Jupiter

  • Coolest and smallest star to produce a superflare found
  • Star is a tenth of the radius of our Sun
  • Researchers led by University of Warwick could only see...

Im Focus: Quantum simulation more stable than expected

A localization phenomenon boosts the accuracy of solving quantum many-body problems with quantum computers which are otherwise challenging for conventional computers. This brings such digital quantum simulation within reach on quantum devices available today.

Quantum computers promise to solve certain computational problems exponentially faster than any classical machine. “A particularly promising application is the...

Im Focus: Largest, fastest array of microscopic 'traffic cops' for optical communications

The technology could revolutionize how information travels through data centers and artificial intelligence networks

Engineers at the University of California, Berkeley have built a new photonic switch that can control the direction of light passing through optical fibers...

Im Focus: A long-distance relationship in femtoseconds

Physicists observe how electron-hole pairs drift apart at ultrafast speed, but still remain strongly bound.

Modern electronics relies on ultrafast charge motion on ever shorter length scales. Physicists from Regensburg and Gothenburg have now succeeded in resolving a...

Im Focus: Researchers 3D print metamaterials with novel optical properties

Engineers create novel optical devices, including a moth eye-inspired omnidirectional microwave antenna

A team of engineers at Tufts University has developed a series of 3D printed metamaterials with unique microwave or optical properties that go beyond what is...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Revered mathematicians and computer scientists converge with 200 young researchers in Heidelberg!

17.04.2019 | Event News

First dust conference in the Central Asian part of the earth’s dust belt

15.04.2019 | Event News

Fraunhofer FHR at the IEEE Radar Conference 2019 in Boston, USA

09.04.2019 | Event News

 
Latest News

New automated biological-sample analysis systems to accelerate disease detection

18.04.2019 | Life Sciences

Explosion on Jupiter-sized star 10 times more powerful than ever seen on our sun

18.04.2019 | Physics and Astronomy

New eDNA technology used to quickly assess coral reefs

18.04.2019 | Life Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>