Organ donor pancreases for the study of human islet cell histology and pathophysiology: a precious and valuable resource

Insulin-secreting beta cells, sophisticated and unique endocrine cells, comprise the majority of cells in the pancreatic islets. Their failure, owing to the interplay of genetic, epigenetic and environmental factors, is key to the onset and progression of type 1 and type 2 diabetes [1, 2]. Therefore, there is much interest in investigating the properties of beta cells in health and disease, with the hope of improving strategies for diabetes prevention and treatment [1‐4]. However, direct evaluation of beta cell features in vivo is substantially impeded by several factors. For instance, the pancreas is located deep in the abdomen, in close vicinity and/or direct contact to vital organs and vessels, and this anatomy makes accessibility extremely limited. In addition, despite much ongoing work, clinical-grade contrast agents and suitable techniques for beta cell imaging are not currently available [5]. Further, owing to the relatively small size of islets, their scattered distribution in the pancreas and the low total amount of beta cells (≤1–2% of the whole pancreatic mass), it is difficult to study this organ. As a consequence, most information on islet and beta cell pathophysiology in humans derives from histological studies.

For the reasons mentioned above, the use of organ donor pancreases in research is being extensively implemented by single research groups and also, very importantly, by dedicated networks. For example, the Network for Pancreatic Organ donors with Diabetes (nPOD; www.​jdrfnpod.​org), which was started in 2007 by JDRF in the USA, has reported use of organ donor pancreases in their research. Similarly, the more recent programme INNODIA (an Innovative Medicines Initiative [IMI] 2 Joint Undertaking, receiving support from the European Union’s Horizon 2020 research and innovation programme and the European Federation of Pharmaceutical Industries and Associations [EFPIA], JDRF, and the Leona M. and Harry B. Helmsley Charitable Trust; https://​innodia.​eu/​) has also adopted use of these samples. However, there are some concerns regarding the use of organ donor pancreases. For instance, the longer the interval between organ removal and tissue processing for clinical or research purposes (CIT), the worse the outcome of pancreas transplant or islet isolation [33]. However, the duration of CIT can be controlled by the operators and is consistently registered, which should avoid the use of organs of poor quality caused by excessive CIT duration. On the contrary, for obvious reasons, research teams have no control of other typical steps in the organ donation timeline, such as the duration of hospital admission prior to brain death and the brain death to organ removal interval, both of which have been suggested to affect the properties of pancreatic non-endocrine and endocrine cells.

Importantly, however, in this edition of Diabetologia, Kusmartseva et al [34] report that duration of hospital time prior to organ donor death does not affect the frequency of cell infiltration into the pancreas or the amount of replicating beta cells, thus reinforcing the validity and value of this precious resource. The authors studied pancreases from 39 organ donors without a history of diabetes and collected sample sections from tissue blocks of the different regions (head, body and tail) of the gland. The donors were age, sex, BMI and ethnicity-matched in groups of three, and within each group, individuals varied in terms of duration of hospitalisation stay prior to organ retrieval (<3 days, 3 to <6 days or ≥6 days). In addition, the authors gathered information on the medications administered prior to death. Single or double immunohistochemistry staining was then performed to identify cells positive for insulin, the leucocyte marker CD45, the macrophage marker CD68 and the replication marker Ki67. The authors found that there were no differences in CD45⁺ and CD68⁺ cell frequencies between hospitalisation groups, suggesting no major impact of hospitalisation stay on the amount of these immune cells in the pancreas. In addition, the interaction of hospitalisation time with age group of organ donors also did not influence the amount of infiltrating immune cells. However, they observed that the frequency of CD45⁺ cells was lower in the head and the body vs tail areas. These regional differences have not been taken into account in a previous study addressing similar issues [35], which interestingly reported that a significantly higher infiltration of CD45⁺ and CD68⁺ in the body portion of the pancreas from organ donors, accompanied prolonged life support (the head and tail were not examined in this report).

Kusmartseva et al also found that length of hospitalisation prior to organ donation did not significantly influence beta cell replication, as assessed by evaluating the presence of the marker Ki67 in insulin positive cells. Cells positive for both insulin and Ki67 staining have been previously observed in surgical pancreatic samples [36] and some (although not all) studies using samples from organ donor pancreases [35, 36]. Interestingly, analyses with autoptic pancreatic specimens have shown extremely low or absent amounts of ‘replicating’ beta cells, suggesting that such a finding could, in part, be an artefact of the postmortem state [37].

In conclusion, whilst each source of pancreatic tissue from humans has advantages and disadvantages (summarised in Table 1), evidence is accumulating, showing that organ donor pancreases are a precious and valuable resource for the study of the histology and pathophysiology of human islet cells. Although the process from donor hospital admission to pancreas retrieval cannot always be fully controlled, the duration of hospital stay until brain death (a major step in the organ donation timeline), does not seem to be associated with significant changes in key histological features of the retrieved pancreas, such as leucocyte and macrophage infiltration, and frequency of replicating beta cells. In addition, in a previous study, duration of final hospitalisation was shown not to be negatively associated with the quality of nucleic acid extracted from organ donor pancreases [38]. However, it must be noted that all the studies that have investigated the correlation between hospital time before brain death and pancreatic histopathological features have been conducted using tissue from donors without diabetes and it is not known whether similarly encouraging findings are applicable to organ donors with diabetes. Furthermore, it must be taken into account that little information, if any, is available on the histology of the human pancreas should the gland come from donors after cardiac death (i.e. with permanent cessation of circulatory and respiratory functions) [39, 40]. In Europe [41] and in the USA [42] there are around 10,000 deceased organ donors per year and only 10–20% of the available pancreases are used for clinical transplantation. More effort should therefore be made to implement the use of donor pancreases for research purposes.