One of the key questions in biology is how external signals guide a cell’s fate. This study shows how apical-basal polarity* plays a crucial role in determining whether immature pancreatic cells differentiate into beta cells or alpha cells, which are the main regulators of our blood sugar levels. The researchers found that changes in cell polarity influence this decision-making process.

Cell Polarity Dictates Cell Fate

First authors Ulf Tiemann and Chenglei Tian employed a novel human stem cell system and advanced tools like single-cell RNA sequencing and gene inactivation to identify the molecular mechanisms governing this process. They discovered that polarized immature pancreatic cells use a specific molecular pathway to increase the levels of cAMP (cyclic adenosine monophosphate), a signaling molecule that transmits external signals to regulate gene activity. More cAMP within cells inhibits the activity of a gene called ARX, which is linked to the development of alpha cells, leading to the birth of beta cells. Conversely, when cells lose their polarity, cAMP levels drop, the ARX gene remains active, and the cells are steered towards becoming alpha cells.

Advancing Cell Fate Research in Other Organs

Applying similar analyses to other developing organs may uncover analogous or entirely new extrinsic cues that govern cell fate decisions.
“Our findings highlight how external signals influence cell identity, and similar mechanisms may be at play in other organs such as the lung, liver, and brain,” says Chenglei Tian.

Potential for Regenerative Medicine and Diabetes Therapies

Understanding how immature pancreatic cells decide whether to become beta or alpha cells opens new possibilities for diabetes therapies. By manipulating these cellular processes, the researchers demonstrated that methods to create new beta cells from stem cells can be improved, potentially leading to more effective, even curative, treatments of individuals with diabetes.

“This discovery gives us a better understanding of how we might control the development of insulin-producing beta cells, which could help in creating better treatments for diabetes,” says Henrik Semb, scientific lead of the study.

*Apical-based polarity refers to the organized structure within a cell that distinguishes its top (apical) side from its bottom (basal) side. This polarity is crucial for proper cell function and positioning.

Original publication:
Tiemann et al., 2025: Pancreatic alpha and beta cell fate choice is directed by apical-basal polarity dynamics. Developmental Cell. DOI: 10.1016/j.devcel.2025.02.008