Human iPS Cell-Derived Insulin Producing Cells Form Vascularized Organoids under the Kidney Capsules of Diabetic Mice

Abstract

Type 1 diabetes (T1D) is caused by autoimmune disease that leads to the destruction of pancreatic β-cells. Transplantation of cadaveric pancreatic organs or pancreatic islets can restore normal physiology. However, there is a chronic shortage of cadaveric organs, limiting the treatment of the majority of patients on the pancreas transplantation waiting list. Here, we hypothesized that human iPS cells can be directly differentiated into insulin producing cells (IPCs) capable of secreting insulin. Using a series of pancreatic growth factors, we successfully generated iPS cells derived IPCs. Furthermore, to investigate the capability of these cells to secrete insulin in vivo, the differentiated cells were transplanted under the kidney capsules of diabetic immunodeficient mice. Serum glucose levels gradually declined to either normal or near normal levels over 150 days, suggesting that the IPCs were secreting insulin. In addition, using MRI, a 3D organoid appeared as a white patch on the transplanted kidneys but not on the control kidneys. These organoids showed neo-vascularization and stained positive for insulin and glucagon. All together, these data show that a pancreatic organ can be created in vivo providing evidence that iPS cells might be a novel option for the treatment of T1D.

Surgical Model of in Vivo Culture of Stem Cells by Implantation of Fetal Organs into Adult Animals

“…Important too that the implantation site was well vascularized: under gland capsules or visceral peritoneum, or within the ear pavilion. Localizations in the spleen or liver or kidney superficial parenchyma are well known and also satisfy to the same criteria [23][24][25][26][27][28][29]. The subcutaneous ear pavilion seems to be an original implantation site and has shown different advantages: simple, easy to perform and not very traumatic operation, well tolerated by animals, allowing visual observation, measures, biochemical and physiological investigations of the implant, procurement of biopsy material.…”

“…They are low cost and simple execution. They are not exclusive: a lot of foetal organs was not tested here such as brain, kidney, lung, and other implantation sites are also possible, many of them having been mentioned in literature [23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38]. Our studies have many common features with organoid creation studies, except that the last are started in vitro and their growth can be obtained from other organs of the same embryonic sheet (for instance intestine crypt cells can give growth to pancreas) by experimental monitoring means [32].…”

The progress of Stem cells in the treatment of diabetes mellitus type 1

“…The iPSCs have been produced from patients with T1D and T2D (Teo et al, 2013). Insulin-producing cells have then been produced in vitro from iPSCs by directed differentiation, using small molecules and growth factors in culture (Raikwar et al, 2015). The advantage of using iPSCs is the absence of ethical concerns, and low risk of teratoma formation (Kanemura et al, 2014).…”

Toward Organs on Demand: Breakthroughs and Challenges in Models of Organogenesis

“…We are witnessing a boom in the generation of miniature organs from iPSCs (33). Cerebral organoids displaying discrete brain regions (34), vascularized and functional liver organoids (35), gastric organoids (36), kidney organoids containing nephrons associated with a collecting duct network surrounded by renal interstitium and endothelial cells (37), and insulin producing pancreatic organoids (38), are only some examples of miniature organs generated on a dish from human iPSCs.…”