What if recreating a pancreas in the laboratory was a reality in the making? This gland attached to the digestive tract which produces digestive juices and hormones is a vital organ of the human body. In a study, published in the journal of cell biology and biochemistry Cella team of Dutch biologists explain that they managed to cultivate for several years pancreatic structures whose functioning is close to that of a human pancreas. The publication was co-signed by Dutch geneticist Hans Clevers, a pioneer in the field of organoids.
A 3D assembly of cells to mimic our organs
Organoids are three-dimensional structures derived from stem cells which mimic cellular composition and organ function. “To do this, in the laboratory, stem cells are cultured in three dimensions and they self-organize according to their cell type.“, indicates Bertrand Pain, research director at the National Research Institute for Agriculture, Food and the Environment (INRAE) and specialist in cerebral organoids. During the formation of the organoid, the stem cells self-organize, that is to say, when a mother cell divides, the daughter cells will be placed in a particular way depending on their proximity .Thus, organoids reproduce architectures similar to those observed in our tissues. .“First of all, the cells form a cyst, a sort of more or less hollow ball. Then, growths appear. Phases of proliferation and differentiation will create buds, making the three-dimensional architecture of the structure more complex. It’s very pretty to watch” ,sourit Bernard Pain. “ And that’s not all, he adds,this assembly must be functional, like the fabric it wants to mimic” .
This functionality can result in the production of hormones or enzymes, for example.
Progress towards complete reproduction of pancreatic tissueAlthough the term “mini-organ” is sometimes used synonymously with organoid, it does not accurately reflect their nature. In particular, the absence of innervation by neurons, connection to the blood circulation and integration with other organs necessarily prevents us from illustrating the functioning of the reference tissue at 100%. “We are talking about pancreatic organoids, rather than “mini-pancreas”! Certainly, their functioning is as close as possible to that of the organ, but it is far from being as complex
” explains Bertrand Pain. The human pancreas has three cell types . On the one hand, there is the exocrine part of the pancreas. It is composed of acinar cells, which form cavities (“acini”) secreting digestive enzymes. These enzymes are transported to the intestine through a set of channels, also called “ducts” of the exocrine pancreas, formed by the ductal cells. On the other hand, the islets of Langerhans bring together the endocrine cells of the pancreas. These are responsible for producing hormones which will circulate in the body
via
blood, like insulin.
If the first work on pancreatic organoids dates from 2013, this new study announces the start of a new chapter for the discipline. Indeed, the team of Amanda Anderson-Rolf, biologist at the Hubrecht Institute, managed to cultivate organoids comprising the three types of pancreatic cells: acinar, ductal and islets of Langerhans. Until now, pancreatic organoids only included one or two cell types at a time. Stem cells: a material with important ethical issues This feat is based on the use of stem cells. There are two ways to obtain stem cells in the laboratory. In the first, scientists use differentiated patient cells
– collected for example following a biopsy – then they give them a pluripotent character again. Stem cells are thus “induced pluripotent stem cells” (IPSCs, for “Induced pluripotent stem cells” in English). The discovery of IPSCs was the subject of the Nobel Prize in Medicine in 2012 awarded to the Japanese Shinya Yamanaka. The second way is to take stem cells from human fetuses. This method was chosen by Amanda Anderson-Rolf and her team. Bertrand Pain specifies that “ these protocols are obviously very ethically supervised“. We can read in the partmethods
from the research article that “human fetal pancreas tissues were obtained with the consent of women who decided to terminate their pregnancies. Their uses for research purposes have been approved by the Dutch Medical Ethics Council of Leiden University Medical Center. A total of 21 tissues were used in this study, collected between the eighth and seventeenth week of gestation“.
The geneticists obtained, in total, 18 organoids from these human fetal tissues which included the three cell types: acinar, ductal and endocrine. In a statement, Amanda Anderson-Rolf added that “
not only did the three cell types form. They also performed the expected functions. Acinar cells release digestive enzymes and endocrine cells produce hormones“. By obtaining functional 3D structures similar to our pancreas, scientists can thus claim to have cultivated pancreatic organoids. “Right now, we’re just beginning to scratch the surface.” Another strength of this paper is the identification of the LGR5 marker, a receptor protein ( Leucine-rich repeat-containing G-protein coupled receptor 5in English), as a key element in the development of human pancreatic tissue. This means that,in vitro,if a stem cell carries the LGR5 receptor on the surface, then it is capable of producing the three pancreatic compartments. “This protein appears in human pancreatic stem cells, but not in mice
Our work highlights the importance of studying human biology, as we could not have made this discovery using animal cells
“, she insists.composition of pancreatic tissue (in %)Credits: Andersson-Rolf et al., 2024, Cell 187, 1–20 (translated figure)These new pancreatic organoids – with their three cellular compartments – offer a new way to study how genes and the environment affect the development and health of the pancreas. Ultimately, their study could contribute to the development of regenerative therapies and new drugs to treat pancreatic diseases. “
We must first fully understand how cells and molecules in the human pancreas work together during development and disease.
“, nuance Amanda Andersson-Rolf. “ Right now, we’re just beginning to scratch the surface.”
By Alice Carliez Stem cell, differentiated cell, cell type… what is differentiation?
Stem cells are like “pupil” cells which do not yet carry out a “specific job”. They have a great potential for differentiation (we speak of pluripotency or multipotency), that is to say they can specialize in many distinct cell types. This process calls for differentiation . A progenitor cell is an immature cell that derives from a stem cell. It is engaged in a path of specialization towards one or a few cell types. A progenitor cell has a limited ability to divide and differentiate into specific cell types.stages of the differentiation process See also:
Video of a pancreatic organoid (Hubrecht Institute)
.Induced stem cells are capable of organizing themselves into 3D structures. This forms an organoid, useful both for carrying out research without using animal models, but also for focusing on the specific case of human cells. Because while connections between mice and humans are common, there are many cases where our bodies react differently from those of these rodents.Illustration of the article: microscopic image of a pancreatic organoid.The nuclei of the different cells are marked in purple and the cyan highlights the acinar cells which secrete digestive enzymes. Credits: Amanda Andersson Rolf and Kelvin Groot
Belgium
