**9. Limitations and future directions**

MSCs have been suggested as an appropriate substitute to islet transplantation for promoting regeneration of endogenous pancreatic progenitor cells to achieve permanent normal blood glucose level in patients with type 1 diabetes [54]. Local RAS in pancreatic islet could regulate PSC differentiation and thus lead to the beneficial outcomes following MSC transplantation. In a study, these kinds of pancreatic progenitor cells have shown to differentiate into insulin-

RAS components like angiotensinogen and renin are expressed after the beginning of pancreatic progenitor cells differentiation, but they are not present in undifferentiated cells. These results indicate that a functional RAS exists in pancreatic progenitor cells and in mature islets that could be modulating cellular differentiation. The mitogenic behaviour related to the Ang II bindings of AT1 receptors has been proposed to regulate reprogramming of pancreatic cells and the differentiation plasticity [55]. However, it is unclear whether AT2 receptor activation reveals counter-regulatory role in this context. Furthermore, it is hypothesized that the ACE2/Ang-(1–7)/Mas axis plays an essential role in pancreatic stem cell differentiation as previous studies have shown the involvement of ACE2 arm in the proliferation and differen-

Regarding the intracellular signalling pathway of Ang II, RAS effect on cardiovascular stem/progenitor cell transplantation has largely been investigated. Among the regenerative medicine-based therapies in the cardiovascular system, induced pluripotent stem cells (iPSCs), which are artificially derived from an adult non-differentiated somatic cell, are a field of research study. In spite of different origin, they resemble ESCs in their growth and gene expression profile [57]. Also, Ang II receptors are expressed in iPSCs, which induce the proliferation and differentiation of pluripotent stem cells to several kinds of stem cells. As mentioned before, Ang II stimulates cell-signalling cascade through ROS production which in turn instigates stem cell proliferation [58]. In a study, the administration of Tempol (ROS generation-blocking agent) in Ang II-treated pluripotent stem cells has attenuated the proliferation of stem cells and DNA synthesis suggesting the role of oxidative-signalling pathway in RAS-associated cell proliferation. The other signalling pathway linked to the differentiation

Ang II is also able to induce ESCs differentiation. In this context, the effect of AT1 receptor activation on collagen IV protein has been investigated [18]. Collagen IV is an extracellular matrix protein having a role in cell adhesion, growth, migration and differentiation. Collagen IV has been shown to be involved in the differentiation of ESCs to smooth muscle cell.

Up-regulation of several transcription factors such as egr-1, c-fos/c-jun, Stat91, NFk-B, which has a fundamental role in stem cell differentiation, is mediated through PI3/Akt pathway. Ang II is the upstream cascade of PI3/Akt82-84. NFk-B is markedly up-regulated in Ang II-treated cells, proposing that there is NFk-B involvement in ESC differentiation

secreting cells.

tiation of other stem cells [56].

164 Renin-Angiotensin System - Past, Present and Future

**8. Current research on the RAS in cardiac stem cells**

of iPSCs and Ang II is JAK/STAT pathway [59].

into the smooth muscle cells [60].

Comprehensive elucidation of the complexity of the regulatory network that drives stem cell therapy will require extensive effort and time. The accretion of daily increasing research and obtained ideas will undoubtedly assist the current research field of stem/progenitor cell therapy. Regenerative progenitor cell therapy has emerged as a possible alternative for pharmacotherapy in different human diseases. A major problem in this field is insufficient efficacy during stem cell transplantation. In order to improve the efficiency of regenerative medicine, researchers examined the impact of the modulation of various cell-signalling pathways, including the RAS. Effects of Ang II in stem cell proliferation and differentiation have been documented in the literature. The presence of the RAS components in progenitor cells and many tissues may regulate growth and development and thus might contribute to the preparation of various progenitor cells for clinical transplantation.
