Periodic Reporting for period 4 - StemHealth (Foetal Intestinal Stem Cells in Biology and Health)
Período documentado: 2021-02-01 hasta 2022-07-31
The objective of the proposed research programme has been twofold. Firstly, we aimed to characterise and investigate the suitability of current sources of epithelial intestinal stem cells for transplantation. Secondly, we wished to define the transcriptional regulatory networks that control the differences observed between an immature foetal state and its adult state in the intestinal epithelium.
Via support from the European Research Council, we have been able to make significant progress towards the identified objectives. Most notably, we have utilized insight into how normal tissue regeneration proceeds using experimental animal models and in patient samples. This has enabled us to direct intestinal epithelial cells isolated from the adult epithelium into a fetal state both via genetically manipulating the cells and via using clinically compliant cell culture components. Importantly, cells in this fetal state efficiently engraft into an injured intestine. Importantly, we went on to show that epithelial cells in this fetal state were inherently more potent than cells in the adult state explaining both why they emerge during tissue regeneration and why these cells efficiently engraft upon transplantation. Collectively, we believe that this insight is critical and will have significant potential for moving cellular therapies into the clinic.
Building upon these seminal findings we demonstrated that the same signaling pathways operate during fetal development (PMID: 35132078) and correlated with the presence of highly potent fetal cell populations that similar to cells responsible for rebuilding the tissues following damage were responsible for growing the tissue during development (PMID: 31092921). The presence of highly potent fetal progenitors was not unique to the intestinal epithelium as quantitative analysis of cells in both the intestine and epidermis revealed their existence, thereby demonstrating that this is most likely a phenomenon shared across tissues (PMID: 31092921 and 31358966). Interestingly, the identified pathways activated via the environment were also exploited during early cancer development, where cells utilized these signaling systems to bypass natural signals that would otherwise induce terminal differentiation (PMID: 36037993).
As a key tool for assessing cell fate and cellular potential we have over the period of the action supported by the European Research Council and aligned with the objectives of the research program optimized protocols for performing transplantation experiments using various animal models. This has been essential for drawing key conclusions related to the utility of new culture conditions (PMID: 29249464), general cellular potential (PMID: 31092921) and in diseases such as tumor development (PMID: 36037993). It is however important to ascertain that such a key methodology was highly reproducible across different research groups. We have therefore published a detailed protocol describing the key parameters for successful transplantation to the colonic epithelium (PMID: 35110738). This is essential for the downstream exploitation of the technology in addressing fundamental research questions, and also to pursue our plan to utilize the basic principles around the methodology to establish cellular therapies for patients with ulcerative colitis.