The new therapeutic strategies that start from a study on diabetes

Diabetes affects more than 100 million people worldwide and its most serious complication, diabetic foot ulcers (DFU), results in an amputation every 30 seconds on average. One of the key reasons behind the unhealing state of DFUs, compared to common skin wounds, is the dysfunction of a group of immune cells called macrophages. These cells change their functions to coordinate wound healing at different stages of the process, but fail to do so if there is diabetic pathology.

On the other hand, the same macrophages, modified due to the growth of a tumor and therefore called Tumour-Associated-Macrophages (Tam), play an essential role in guiding the development of the tumor itself, by secreting factors that promote the formation of vessels blood vessels and inhibit the immune attack. These are precisely the characteristics one would like to have for macrophages associated with foot ulcers in diabetics; but how can they be obtained in diabetes, instead of cancer?

A new job indicates a possible answer. A group of researchers hypothesized that tumor macrophages release some factors capable of enrolling other macrophages, giving them the characteristics of Tams. Following this assumption, the researchers designed and optimized suitable experimental protocols, until verifying that normal mouse bone marrow-derived macrophages can acquire a new set of pro-regenerative functions after co-culture with Tams. When transferred to the wound of diabetic mice, these cells potently induced cell proliferation, resolved inflammation, and orchestrated vascularization of typically non-healing wounds; with this, it has been shown that the functions induced by the tumor, if transferred to a different context, can really be useful for healing.

However, it is unthinkable to use for therapy a preparation that also contains tumor cells; the researchers therefore first of all proceeded to investigate by RNA sequencing on single cells in what the macrophages “educated” by Tam cells differed, i.e. what type of proteins had been activated by the coculture process, to try to isolate those potentially implicated in the healing.

This has led to theidentification of multiple factors that endow normal macrophages with reparative capacities. By isolating nine of the most promising ones, a mixture was obtained to which the cells from which the macrophages originate, i.e. the monocytes, were exposed (this time choosing human cells): in this way, it was demonstrated that human macrophages were obtained with reparative capacity, completely abandoning the use of any component derived from the tumor (including Tam) e paving the way for a clinical development of a new cell therapy for the diabetic foot.

The road to this result is naturally long; here, however, I would like to highlight an aspect that I find interesting. Through the use of the correct set of biochemical signals, in this case proteins, a desired function has been achieved; the fact that this set of signals is used in nature by tumor cells to protect and promote the growth of a cancer is by no means an obstacle to its reuse in a different contextin which the biochemical machine that sustains life responds in the same way, but obtaining a beneficial result.

At the molecular level, that is, the processes that control the activity of living systems are modular: reusing what is of interest in an appropriate way, after having elucidated its function in its natural context, allows in this case to repair a physiological process destroyed by a pathology.

This is how, increasingly, modern medicine works: the understanding of one or more molecular mechanisms allows the design of therapeutic strategies that recompose physiological signaling pathways in the right way, in order to rectify a specific biochemical process. For this purpose, it can also be a tumor that “teaches” how a certain useful mechanism works; because knowledge, wherever acquired, can prove useful in surprisingly unexpected ways, thanks to the integration and internal coherence of the picture returned to us by scientific research.