Study reveals glucose’s surprising role as master manipulator of tissue maturation

Amazing stuff!

"... [Glucose] by binding in its intact form to proteins that control which genes in the genome are made into proteins and when.

The discovery of glucose’s undercover double life was so surprising the researchers spent several years confirming their findings before publishing their results.

“At first we just didn’t believe it,” ... “But the results of extensive follow-up experiments were clear: Glucose interacts with hundreds of proteins throughout the cell and modulates their function to promote differentiation.” ...

They found that human skin organoids – engineered skin tissue grown in liquid that mimic the cellular composition and organization of native skin – were unable to differentiate properly when glucose levels were lower than normal. A closer look found that the expression of over 3,000 genes in the cells was affected by the low glucose levels; many of these genes encoded proteins known to be involved in skin differentiation. ...

found that glucose levels increase due to a boost in production of a protein that transports glucose from the outside of the cell to its interior. Once inside, glucose binds to hundreds of proteins, including one called IRF6, that increase the expression of many genes involved in differentiation. When glucose binds to IRF6, it causes the protein to change its conformation in a way that changes its ability to influence gene expression and drive differentiation. ..."

From the highlights and abstract:

"Highlights

• Intracellular free glucose accumulates during differentiation

• Elevation of free glucose is essential for epidermal differentiation

• Glucose physically associates with numerous proteins, including the IRF6 TF

• Glucose enables IRF6 dimerization, genomic localization, and target gene induction

Summary

Non-energetic roles for glucose are largely unclear, as is the interplay between transcription factors (TFs) and ubiquitous biomolecules. Metabolomic analyses uncovered elevation of intracellular glucose during differentiation of diverse cell types. Human and mouse tissue engineered with glucose sensors detected a glucose gradient that peaked in the outermost differentiated layers of the epidermis. Free glucose accumulation was essential for epidermal differentiation and required the SGLT1 glucose transporter. Glucose affinity chromatography uncovered glucose binding to diverse regulatory proteins, including the IRF6 TF. Direct glucose binding enabled IRF6 dimerization, DNA binding, genomic localization, and induction of IRF6 target genes, including essential pro-differentiation TFs GRHL1, GRHL3, HOPX, and PRDM1. These data identify a role for glucose as a gradient morphogen that modulates protein multimerization in cellular differentiation."

Study reveals glucose’s surprising role as master manipulator of tissue maturation | Stanford Report "The discovery, based on extensive Stanford Medicine research, has implications for the treatment of diabetes and cancers."

Glucose modulates IRF6 transcription factor dimerization to enable epidermal differentiation 

Graphical abstract:

How stem cells organize cellular replacements at a distance

Amazing stuff!

"... it has remained unclear whether stem cells located in different areas of our tissues are able to communicate with each other across distances, telling each other where and how many cells need to be replaced. ...

In a new study ... to show that adult stem cells in skin tissue are able to coordinate calcium signals at surprisingly long distances to prompt the replacement of lost cells.

The ... team ... found that localized groups of up to 10 stem cells initiate communication via calcium signals. As seen in this video (above), these small groups of stem cells, located in a thin layer of the skin known as the epithelial tissue (labelled with magenta with calcium levels in green fluorescence), launch coordinated tissue-wide communications which dictate where and when lost cells are replaced. ...
This biological insight was made possible by a computational method known as “Geometric Scattering Trajectory Homology,” developed by the research team, which captures the patterns of signaling at multiple spatial and temporal resolutions. This method is broadly applicable, and the researchers are now applying it to decipher additional complex signaling in various other biological systems in a follow-up paper. ..."

From the abstract:

"Skin homeostasis is maintained by stem cells, which must communicate to balance their regenerative behaviors. Yet, how adult stem cells signal across regenerative tissue remains unknown due to challenges in studying signaling dynamics in live mice. We combined live imaging in the mouse basal stem cell layer with machine learning tools to analyze patterns of Ca2+ signaling. We show that basal cells display dynamic intercellular Ca2+ signaling among local neighborhoods. We find that these Ca2+ signals are coordinated across thousands of cells and that this coordination is an emergent property of the stem cell layer. We demonstrate that G2 cells are required to initiate normal levels of Ca2+ signaling, while connexin43 connects basal cells to orchestrate tissue-wide coordination of Ca2+ signaling. Lastly, we find that Ca2+ signaling drives cell cycle progression, revealing a communication feedback loop. This work provides resolution into how stem cells at different cell cycle stages coordinate tissue-wide signaling during epidermal regeneration."

How stem cells organize cellular replacements | YaleNews In a new study, Yale scientists reveal insights into how stem cells communicate with one another to coordinate the replacement of lost cells.

Cell cycle controls long-range calcium signaling in the regenerating epidermis (open access)

Fig. 1 The epidermal stem cell layer cohesively carries out coordinated Ca 2+ signaling at long range.