Cell therapy has emerged as a potential therapeutic strategy in regenerative disease. Among different cell types, mesenchymal stem/stromal cells have been wildly studied in vitro, in vivo in animal models and even used in clinical trials. However, while clinical applications continue to increase markedly, the understanding of their physiological properties and interactions raises many questions and drives the necessity of more caution and supervised strategy in their use. 1. Introduction Since the discovery of pluripotent embryonic stem cells (ESCs) derived from the inner cell mass of blastocysts of embryos, stem cells have been defined by two principal characteristics: self-renewal and ability to differentiate in various cell types. The interest in stem cell use for clinical therapy and regeneration has been growing due to their ability to differentiate into various functional cell types. Among stem cells, two classes can be distinguished: pluripotent stem cells such as embryonic stem cells and induced pluripotent stem cells (IPSCs) [1] and multipotent stem cells with more restricted differentiation capacities, often referred to as adult stem cells. The source of ESCs and the methods used to generate IPSCs [2] together with the risk of teratoma formation [3] raise ethical and safety issues for the clinical use of ESCs and IPSCs [4]. Among adult stem cells, mesenchymal stem/stromal cells (MSCs) are the main seed cells used in regenerative medicine and are an expanding area of research, over the past decade, due to their unique biological properties. These properties cover a large spectrum ranging from immune modulation, local signaling to differentiation abilities. It has been demonstrated in vitro that MSCs can differentiate into osteoblast, chondrocyte, adipocyte, and hepatocytes/cardiomyocytes-like cells. But the use of these cells in numerous preclinical trials raises multiple questions/dilemmas that we will try to address in this review.(i)Are these cells sufficiently defined and are they true stem cells?(ii)Should MSCs isolated from different tissues be considered as equivalent?(iii)What are their major characteristics?(iv)Can we use them in clinical trials and if so what should be the context? 2. How Do We Define Mesenchymal Stem Cells? 2.1. Mesenchymal Stem Cells: Is It Appropriate? Nonhematopoietic cells in the bone marrow were first isolated by Friedenstein et al. in 1968 [5] and defined as spindle-shaped, fibroblast-like multipotent cells capable of colony-forming unit-fibroblast (CFU-F). The studies in the following decade better defined
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