**4. The RAS and mesenchymal stem cells**

during growth, proliferation and differentiation of stem cells. Improvement of the stem cell functionality and making them ideal candidates in different kinds of disorders has been a new research field in the last decade. Meanwhile, the effect of RAS on stem cell growth, proliferation and function is an emerging attempt among researchers. Ang II receptor activation increases the proliferation of several progenitor cells, such as mouse bone marrow-derived stem cells and human cord blood cells. Accordingly, manipulation of the RAS may alter

The term stem cell stands for the population of immature precursor cells, which are able to renew themselves and be the source of de novo replacement for many body tissues. Stem cells are classified into two main groups: embryonic stem cells (ESCs) and adult stem cells. ESCs can be obtained from the inner cell mass of the embryonal blastocyst. Although they are easily achieved, some disadvantages restrict their application. Adult stem cells such as mesenchymal and haematopoietic stem cells (HSCs) are obtained from mature tissues. Due to their plasticity, adult stem cells produce cell lineage different from their original organ. Thus, adult stem cells seem to be an appropriate candidate for organ regeneration in different kinds of diseases or lost/damaged organs. **Table 1** represents the main stem cell and their advantages

**Stem cell type Origin Advantages Disadvantages**





ESCs are pluripotent cells capable of differentiation into different cells such as cardiomyocytes, and endothelial cells have been considered as a source of regenerative medicine [1]. For instance, ESC-derived endothelial cells have therapeutic effects via the increment of angiogenesis and heart functionality [2]. PI3/Akt-signalling pathway has been shown to be linked with human ESC-derived cardiomyocyte proliferation in vitro [3]. RAS stimulation activates PI3/AKT pathway, while the inhibition of RAS increases Akt phosphorylation [4], which

and/or have beneficial effects on the efficacy of stem cell therapy.

**2. Stem cells**

160 Renin-Angiotensin System - Past, Present and Future

and disadvantages.

**3. The RAS and ESCs**

Embryonic stem cell Blastocyst stage of an

embryo

**Table 1.** Main stem cell and their advantages and disadvantages.

Adult stem cell Mature tissue - Easily obtained

Mesenchymal stem cells (MSCs) as multipotent cells are mainly found in bone marrow and adipose tissue and can differentiate into various cell types [9]. Simple isolation, high immune prevalence and angiogenic-inducing properties have made MSCs suitable candidates for stem cell therapy of different kinds of diseases [10]. Besides, these MSCs exert paracrine effects causing the modulation of a large number of cellular responses, such as survival, proliferation, migration and gene expression [11]. Diminishing oxidative stress and suppression of the TGF-β/Smad2-signalling pathway are some of these paracrine effects [12, 13]. In the rat pulmonary hypertension model, MSCs have shown superiority regarding the lowering of blood pressure and ventricular overload; hence, MSC transplantation in chronic lung disease with pulmonary hypertension has pointed towards a new therapeutic option [14]. Concomitant percutaneous trans-luminal renal angioplasty with MSC therapy has been reported to decrease inflammation, fibrinogenesis and vascular remodelling in atherosclerotic renal artery stenosis of swine [15]. Also, MSCs have the ability to recognize inflammation lesions, and Ang II effects the migration and homing of these cells to the site of injury [16]. Dysregulation of the RAS decreases the paracrine therapeutic potential of MSCs [17].

Expression of renin, AT1 and AT2 receptors has been implicated with the regulation of MSCs differentiation to adipocytes, while the differentiated cell produces significant amounts of endogenous RAS [18]. Indeed, endogenous blockade of AT1 receptor inhibited adipogenesis of MSCs [18]. These outcomes are in line with clinical observations that RAS blockade acts as a protective factor against the onset of obesity-induced diabetes mellitus type 2 [19]. Ang II also has been shown to stimulate the synthesis of vascular endothelial growth factor (VEGF) that is an angiogenic agent in MSCs [20]. Additionally, MSCs have been suggested as a promising regenerative medicine for treating ischaemic heart disease and diabetes [21]. Hence, it is probable that Ang II-induced production of VEGF might be a contributing underlying mechanism of the beneficial consequences obtained following MSC transplantation.
