Pancreatic Diseases: The Role of Stem Cells

Abstract

Mesenchymal stem cells (MSCs) may be isolated from adipose tissue, bone marrow, umbilical cord, and peripheral blood. They are characterized by their innate ability to self-renew as well as differentiate into a variety of cell types. Several studies have demonstrated the innate characteristic of MSCs to home to sites of injury, inflammation, ischemia, as well as to tumors and metastases, including pancreatic gland inflammatory processes and pancreatic carcinoma, which renders them as an attractive option for cell-based therapy of these conditions.

Mesenchymal stem cells may have a crucial role in cell-based therapy of tumors, by specifically targeting certain aspects of tumor’s biology, either by introducing into the tumor genes, which interfere with specific molecular pathways or induce apoptosis, or by introducing specific genes, which contribute to the local activation of systemically administered prodrugs, avoiding thus the side effects, which are caused by the systemic administration of chemotherapy.

Recent studies have demonstrated that the inhibition of the anti-apoptotic X-linked inhibitor of apoptosis protein (XIAP), by using RNA interference, causes an enhanced TRAIL (tumor necrosis factor-related apoptosis-inducing ligand)-induced apoptosis in pancreatic cancer cells, both in vitro and in vivo. Moreover, by combining XIAP inhibition and human MSCs (hMSCs) expressing sTRAIL (the soluble form of TRAIL), the apoptotic activity was not only limited to slowing the tumor growth but also caused tumor’s remission and inhibition of metastatic growth. Alternatively, the production of IFN-b within the tumor site, by genetically modified MSCs, has been shown to suppress tumor growth to a significant extent.

The concept of gene-directed enzyme prodrug therapy, also called suicide gene therapy, in cancer therapy, has been under investigation in recent years. This approach consists of two steps: firstly, the use of genetically engineered MSCs as carriers of a specific gene that encodes a prodrug-activating protein and, secondly, the systematic administration of that particular prodrug that will be metabolized and activated into cytotoxic metabolites within the tumor. Given that angiogenesis is essential for tumor initiation and growth, genetically modified MSCs that express a therapeutic transgene under the control of TIE2 promoter upon reaching the tumor and in the presence of angiopoietin – 2 (ANGPT2) ligand, have been implicated in targeting the angiogenesis pathway, with the herpes simplex virus thymidine kinase (HSV-tk) being the most commonly used transgene. This mechanism of action, combined with the prodrug ganciclovir (GCV), resulted in a significant decrease in the volume of the pancreatic tumor. Alternatively, CC chemokine ligand 5 (CCL5) represents, among other chemokines, an essential factor in the homing process of MSCs to sites of tissue injury, including tumors and their metastases. Genetically modified MSCs to express the HSV-tk transgene under the control of the CCL5 promoter, combined with GCV as a prodrug, resulted in a significant decrease in the growth of the primary pancreatic tumor, as well as in a significant decrease in the incidence of metastatic lesions, in a mouse orthotopic model of pancreatic carcinoma.

In the context of acute pancreatitis, bone marrow MSCs (BM-MSCs) were the most commonly used MSCs, with nearly all studies demonstrating the immunomodulatory effect of BM-MSCs, by downregulating the expression of several pro-inflammatory markers and cytokines. Apart from their immunomodulatory effects, another potential mechanism of action of BM-MSCs is their antioxidant activities, by increasing the expression of glutathione peroxidase and superoxide dismutase. The therapeutic effect of BM-MSCs in acute pancreatitis is not only limited to the pancreatic gland, as BM-MSCs exert also their effects in other organs, including the improvement in the small intestinal capillary endothelial barrier.

On the other hand, only a limited number of studies have investigated the potential effect of MSCs administration for the treatment of chronic pancreatitis. Apart from the immunomodulatory effects of MSCs, all studies demonstrated a decrease both in the pancreatic damage and in the pancreatic fibrosis, following the administration of MSCs. Moreover, the administered BM-MSCs and umbilical cord-derived MSCs exerted an anti-apoptotic effect, by decreasing the apoptotic rate of the pancreatic acinar cells, as has been shown in two studies.

To date, there are certain limitations of cell-based therapies, which need to be carefully considered and require further investigation. First but not least, stem cells for therapeutic application need to meet the standards of Good Manufacturing Practice regulations, posing as important quality criteria, among others, the immunophenotype of the cells, the composition of the culture medium, and the risk for malignant transformation, as well as the aging and the immunosuppressive potential of the manufactured MSCs. Another issue regards the correct amount of MSCs that should be systemically administered, so as to home to the targeted tumor and exert their therapeutic effect. Several studies have focused on that issue, with some studies estimating the necessary amount of administered MSCs to be less than 10% of the targeted tumor mass.

At this point, it should be emphasized that the majority of studies investigating the insertional mutagenesis phenomenon are performed in rodent models, which have a relatively short life span, so that the true mutagenic risk cannot be estimated in the long-term. Therefore, the use of primate animal models, with a relatively longer life span, which may be administered greater amounts of MSCs, and possibly in a repeated fashion, will elucidate the true mutagenic risk of MSCs used for cell-based therapies.