June 29, 2022

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Nature Medicine: Human fetal intestinal endocrine cells can express insulin

Nature Medicine: Human fetal intestinal endocrine cells can express insulin



Nature Medicine:  Scientists have discovered for the first time that human fetal intestinal endocrine cells can express insulin, and the treatment of diabetes may usher in a fundamental breakthrough.

Speaking of insulin, everyone is familiar with it. As the only hormone in the human body that has the effect of lowering blood sugar, the absolute or relative lack of insulin secretion is an important cause of diabetes .

We all know that insulin is synthesized and secreted by pancreatic β-cells . For some patients with almost complete loss of pancreatic β-cell function, they can only rely on injections of exogenous insulin to maintain a stable blood sugar level in the body.

But after all, exogenous sources are not as good as self-secretion. In addition, many patients cannot take injections strictly and regularly.

There are not many patients who can really maintain blood sugar levels well.

Islet transplantation is another option for patients with loss of islet function, but since it is an operation, there are risks, and there is still no guarantee that transplantation will be successful, so few patients choose islet transplantation.

Therefore, scientists considered that if other cells in the human body can secrete insulin after induction, wouldn’t it be a perfect solution to the problem ?

Recently, the team of Professor Shalev Itzkovitz from the Weizmann Institute of Science in Israel and the team of Professor Liza Konnikova from Yale University have joined forces to try to find new insulin-secreting cells.

They performed single-cell sequencing of human fetal intestinal cells and found that during the embryonic period, the fetal intestinal K/L cells expressed insulin gene expression. After the fetus is born, the expression of the insulin gene disappears .

Related work was recently published in the journal “Nature Medicine” [1].

Nature Medicine: Human fetal intestinal endocrine cells can express insulin

▲ Screenshot of the cover of the paper

In fact, studies have found that human pancreas and small intestine have a common tissue origin . In an embryo at 5 weeks of gestation (GA), the pancreas and small intestine develop together from the foregut-midgut boundary [2].

The secretion mechanism of intestinal endocrine cells and pancreatic islet endocrine cells are also very similar [3].

Therefore, researchers believe that intestinal cells may have the potential to secrete insulin.

We already know that there is no expression of insulin gene in mature intestinal cells .

Therefore, the researchers performed single-cell-level RNA sequencing on 4 fetal intestinal samples around 20 weeks of gestation and 2 neonatal intestinal samples .

After sequencing, the intestinal cells were divided into 11 subgroups, among which the high expression of insulin gene (INS) was found in the intestinal endocrine cell group of the fetal group .

However, there are many types of intestinal endocrine cells. In order to study which types of cells express the insulin gene, the researchers re-clustered the intestinal endocrine cells and found that the insulin gene is mainly expressed in fetal intestinal K/L cells. . Nine out of 37 intestinal K/L cells express the insulin gene .

Nature Medicine: Human fetal intestinal endocrine cells can express insulin

▲ Single cell sequencing results of intestinal cells and intestinal endocrine cells

Intestinal K/L cells include K cells and L cells. In single-cell sequencing, these two types of cells are usually clustered into a subgroup.

Intestinal L cells can secrete GLP-1 (glucagon-like peptide-1) , and activation of GLP-1 receptor can promote insulin release.

Although intestinal L cells are closely related to insulin secretion, it has not been found that L cells can express the insulin gene before .

To further verify this phenomenon, the researchers performed single-molecule fluorescence in situ hybridization (smFISH) on fetal intestinal tissue and neonatal intestinal tissue.

It was found that 4 out of 14 fetal tissue samples (INS+ cells) observed high expression of insulin mRNA and protein , but no insulin mRNA and protein expression was observed in all neonatal tissue samples.

Similar to pancreatic β cells, INS+ cells show obvious intracellular polarization (the expression of insulin mRNA is located on the top side of the cell, and the expression of insulin protein is located on the base side of the cell) .

Nature Medicine: Human fetal intestinal endocrine cells can express insulin

▲ Expression of insulin gene and protein in fetal intestinal tissue

Although high expression of insulin gene has been observed in fetal intestinal tissues, the specific functions of these cells in embryonic development and insulin synthesis and secretion are still unknown .

Itzkovitz and his colleagues speculate that because INS+ cells are not detected in all fetal intestinal samples, they may not have the necessary physiological functions .

But there is no doubt that the discovery of these cells has greatly promoted our understanding of insulin .

Perhaps one day, these dormant insulin production procedures will be awakened in diabetic patients, so that some diabetic patients can be cured in a real sense.

references:

1.Egozi A, Llivichuzhca-Loja D, McCourt BT, Bahar Halpern K, Farack L, An X, Wang F, Chen K, Konnikova L, Itzkovitz S. Insulin is expressed by enteroendocrine cells during human fetal development. Nat Med. 2021 Dec;27(12):2104-2107. doi: 10.1038/s41591-021-01586-1. Epub 2021 Dec 9. PMID: 34887578.

2.Jennings RE, Berry AA, Strutt JP, Gerrard DT, Hanley NA. Human pancreas development. Development. 2015 Sep 15;142(18):3126-37. doi: 10.1242/dev.120063. PMID: 26395141.

3.Habib AM, Richards P, Cairns LS, Rogers GJ, Bannon CA, Parker HE, Morley TC, Yeo GS, Reimann F, Gribble FM. Overlap of endocrine hormone expression in the mouse intestine revealed by transcriptional profiling and flow cytometry. Endocrinology. 2012 Jul;153(7):3054-65. doi: 10.1210/en.2011-2170. Epub 2012 Jun 8. PMID: 22685263; PMCID: PMC3440453.

Nature Medicine: Human fetal intestinal endocrine cells can express insulin

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