Original paperAdipose derived cellsAdipose tissue-derived mesenchymal stromal cells efficiently differentiate into insulin-producing cells in pancreatic islet microenvironment both in vitro and in vivo
Introduction
Cell-based treatments, which involve the replacement, repair or enhancement of the biological function of a damaged organ or tissue, have appeared as a potent treatment strategy for many diseases. Stem cells are recognized as a main biological material, which could be delivered into the damaged site to recover the functionality of the tissue.
Although there are a number of stem cell types characterized, adult stem cells are much preferred because of their availability and the existing ethical concerns. For that reason, adult stem cells such as mesenchymal stromal cells (MSCs) have been used in the experimental studies in the treatment of type 1 diabetes mellitus. One of the most important characteristics of MSCs is their differentiation into various non-hematopoietic tissues such as muscle, cartilage, bone, liver, nerve, heart, brain, adipose tissue and insulin-producing cells (IPCs) both in vivo and in vitro 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11. On the other hand, MSCs were also shown to have an immunomodulatory effect to suppress immune response in autoimmune and inflammatory diseases such as diabetes 11, 12, 13, 14. Their effects include suppression of T-cell and B-cell proliferation, induction of regulatory T cells, and influencing NK cell and dendritic cell maturation and function. For this reason, MSCs have the potential to be used in the possible cell-based treatment of type 1 diabetes.
The differentiation or reprogramming of stem cells could be achieved by remodulating the microenvironment (niche), which regulates the fate of cells through soluble factors and contacts. By providing the suitable microenvironment similar to in vivo, differentiation of stem cells into the desired cell types with full functionality can be obtained in vitro 8, 15, 16, 17, 18, 19, 20, 21. In an attempt to generate IPCs, Choi et al. (22) prepared rat pancreatic extract from the pancreas, in which the regeneration process was induced by partial pancreatectomy, and this extract was used to differentiate MSC into IPC in vitro. With the use of the same approach, adipose tissue–derived stem cells also were shown to differentiate into IPCs (23). These studies showed considerable success in the IPCs production. Unfortunately, the approach did not highlight the real factors for the differentiation of the stem cells. To refine these approaches, instead of using pancreatic extracts, we used isolated rat pancreatic islets and achieved differentiation of rat bone marrow (rBM)-MSCs into IPCs (8).
In this study, we aimed to compare the insulin producing capacities of differentiated MSCs derived from different tissues. The differentiation of MSCs derived from rat adipose tissue (rAT) and rBM were analyzed by means of in vitro and in vivo co-culture experiments. The insulin-producing capacities of pancreatic islets transplanted under the renal kidney capsule in the presence of mesenchymal stromal cells derived from adipose tissue and bone marrow were compared, and the recovery of the blood sugar levels in hyperglycemia rat models were examined.
Section snippets
Animals
Wistar Albino rats (220–240 g) were obtained from the Experimental Animal Center of Kocaeli University (Kocaeli, Turkey). The use of animals and animal protocols were approved by the local animal care committee according to the institutional guidelines and national animal welfare.
Isolation and culture of rAT-MSCs
Rats (n = 4) were anesthetized by injection of xylazine (10 mg/kg; Alfazyne, Alfasan Int, Woerden, The Netherlands) and ketamine hydrochloride (75 mg/kg; Ketalar, Pfizer, Luleburgaz, Turkey). Periperitoneal adipose
Cell cultures of rAT- and rBM-MSCs
Isolated cells from rAT and rBM distributed sparsely on the culture flasks and displayed mostly fibroblast-like, spindle-shaped morphology during the early days of incubation. Small colonies, called colony-forming units, appeared within 4–7 days, and these primary cells reached monolayer confluence within 12–15 days. In the later passages, most of these MSCs exhibited large, flattened or fibroblast-like morphology (Figure 1A1–A3, B1–B3).
Flow cytometry identification of rAT- and rBM-MSCs
The cell analysis data indicated that rAT- and rBM-MSCs
Discussion
Despite that MSCs represent a rare population in bone marrow stroma and other tissues, they might be used in an allogenic setting in the future because they are clonogenic (expand in vitro) and have a low immunogenicity, allowing allogenic transplantations. For this reason, they might be a good choice in stem cell therapy of type 1 diabetes. In the previous studies relating to the role of MSCs in the regeneration of β cells, it was shown that they can differentiate into β cells under certain
Acknowledgments
This study was supported by the Scientific and Research Council of Turkey (TUBITAK, Grant No. 107S276), Kocaeli University (Grant No. 2008/5) and Turkish Diabetes Foundation (Grant No. 2010/1).
Disclosure of interests: The authors have no commercial, proprietary, or financial interest in the products or companies described in this article.
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