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  • The incremental reduction albeit not


    The incremental reduction, albeit not statistically significant, in collagen I with LCZ696 compared to perindopril treated animals, may therefore be related to a more compliant ventricle in LCZ696-treated animals. This is not so surprising given the incremental anti-fibrotic effect of the active metabolite of sacubitril, LBQ657, in cardiac fibroblasts when added to valsartan following angiotensin II stimulation [9]. Similar incremental anti-hypertrophic effects with LBQ657 were observed in angiotensin II-stimulated cardiac myocytes [9]. The benefit which may be in part due to reduced pro-N terminal Candesartan derived natriuretic peptide and reduced left atrial volume as observed in HF patients with preserved EF [22].
    Conclusions The following is the supplementary data related to this article.
    Grant support National Health and Medical Research Council of Australia (NHMRC Program Grants 546272, 1092642), and Novartis (investigator-initiated trial agreement) and gift of LCZ696. TVL was supported by post-doctoral research Candesartan grant 2011062 from the South-Eastern Norwegian Health Authority.
    Conflict of interest
    Introduction Diabetes mellitus (DM) is one of the health problems worldwide; the number of people having DM is increasing continuously. This increase in the prevalence of diabetes is alarming because it will also raise the percentage of deaths resulting from different diabetic complications such as cardiovascular complications, neuropathy, and nephropathy. World Health Organization documented that over than 80% of deaths resulted from DM occur in the countries of middle and low income [1]. Type 1 diabetes mellitus (T1DM) is an autoimmune disease which is caused by the destruction of pancreatic β-cells, thus it requires a daily insulin injection and blood glucose level monitoring. The insulin injection may be accompanied with uncontrolled blood glucose level and this leads to many severe complications including retinopathy, neuropathy, nephropathy, atherosclerosis, and heart diseases. Islet transplantation could be a permanent cure for T1DM if the transplanted islets could control the blood glucose level and overcome graft rejection resulted from the immune and inflammatory reactions. The limited sources of islets available for transplantation and the unsuccessful means for overcoming the rejection of transplanted islets after transplantation are considered the most two important obstacles, which hinder the widespread application of islet transplantation [2], [3]. To overcome the problem of limited sources of islets, the islets from alternative species have been used in addition to the in vitro generation of insulin-producing cells (IPCs) and islets from stem cells. Porcine islets have been reported as a potent alternative to islet transplantation in combination with biological means to prevent the rejection of xenografts [4]. Stem cells met great success as a novel regenerative medicine tool for the human islet transplantation. The IPCs can be obtained from different types of stem cells (hematopoietic stem cells, HSCs; mesenchymal stem cells, MSCs; embryonic stem cells, ESCs; and induced pluripotent stem cells, IPSCs; etc.). Caution should be taken into consideration when using ESCs because their differentiation cannot be 100% and the remaining undifferentiated portion may cause tumorigenicity. Apart from the ESCs which are isolated from the early embryo, there are other types of stem cells which can be isolated from the mature tissues of mammals. These adult stem cells can be self-renewed indefinitely and they possess more restricted differentiation potential [3]. Bone marrow (BM) contains different adult stem cells such as HSCs which give rise to the different types of blood cell, and MSCs which give rise to the nonhematopoietic tissues [5], [6]. BM is considered the primary source of MSCs, but there are other sources of MSCs such as adipose tissue [7], human umbilical cord blood [8], and skeletal muscle [9]. However, MSCs derived from sources other than BM exhibit restricted differentiation potential [10]. Compared to ESCs, MSCs possess fewer ethical concerns of their sources and they are less potent to cause teratoma due to their restricted differentiation potential. Moreover, MSCs possess self-renewal potential, multilineage capacities, immune-modulatory effects, and paracrine effects. These characteristics of MSCs make them a great candidate for cell therapy and regenerative medicine including human islet transplantation [11], [12]. A careful choice of source of stem cells, methods of isolation, growth factors, and mechanisms of differentiation may all be contributing factors to the successful production of IPCs for the islet transplantation [13].