PLoS Genet. 2020; 16(10): e1009069. doi: https://doi.org/10.1371/journal.pgen.1009069
The authors used mouse conditional gene knock-out models to investigate the role of Insulin-like growth factor-2 (Igf2) in pancreatic growth and function. When Igf2 was deleted specifically in mesenchyme-derived cells (but not when deleted in exocrine and endocrine cells), the entire pancreas was smaller and showed reduced exocrine and endocrine functions. These mice showed postnatal whole-body growth restriction and the female mice developed glucose intolerance when they became pregnant. Conversely, increased IGF2 levels in the mesenchyme-derived cells increased pancreatic size.
There is a fascinating specificity in the regulation of some key tissues and organs. First, Igf2 is a member of a small number of imprinted genes, which are active only on one parent-specific inherited copy. Hence, in this study, the consequences of Igf2 genetic engineering were only seen when they disrupted the function of the paternally-inherited gene - for some reason, the maternally-inherited Igf2 gene is naturally silenced. Second, the key findings of this study show that, within the pancreas, Igf2 is needed only in mesenchyme-derived cells. This understanding was made possible by the recent availability of mesenchyme-specific gene silencing tools. It is intriguing to find that, although Igf2 is clearly needed for normal exocrine and endocrine cell function, its expression is redundant within those cells. Instead, Igf2 is crucially active in the surrounding mesenchyme-derived stromal cells.
Stroma derives from Greek, meaning a layer or bed cover, and stromal cells typically contribute to connective tissues and organ structure. However, we are increasingly learning about other key functions of stromal cells, beyond their supportive anatomical characteristics. Other examples include the crucial roles of glial cells in neuronal cell function, and ovarian granulosa cells that surround oocytes. Notably, these authors also found that the expression of other key growth-related imprinted genes, such as Plagl1/Zac1, were highly enriched in the mesenchyme, and they hypothesize that genomic imprinting may have evolved a particular role in mesenchymal-specific function.