**1. Introduction**

Clinical use of stem cells is rapidly growing in recent years because of their capabilities to repair and regenerate tissues and organs of body [1]. Stem cells have self-renewal potential and can differentiate into cells of multiple lineages under appropriate conditions. They can secrete a large number of bioactive molecules that are involved in repair and regeneration of damaged tissues and organs. Based on their potential, stem cells are classified as totipotent, pluripotent, multipotent and unipotent. Fertilized eggs (zygote) are totipotent as they can make cells of all three lineages and extra embryonic tissue such as placenta. Embryonic stem cells (ESC) are derived from inner cell mass of 5 days old embryos and are pluripotent as they have potential to differentiate into all cells and tissues of the body except placenta. MSC are the most widely used cells and they can be isolated from various adult body tissues (bone marrow, adipose tissue, articular cartilage, synovium, synovial fluid, dental pulp, etc.) as well as from neonatal stem cell sources (cord blood, cord tissue, placenta) [2]. Currently, hundreds of clinical trials have been registered using MSCs (www.clinicaltrials.org) for various conditions such as degenerative brain disorders, stroke, cardiac dysfunctions, myocardial ischemia, renal disorders, wound healing, diabetes etc. [3]. MSCs exert their effect either by

transdifferentiation into respective tissues and/or through their paracrine effects by releasing different cytokines and growth factors [4].

The potential of adult stem cells such as MSCs is severely compromised in vitro by culture conditions and by number of passages of the cells [5]. In addition, "disease conditions" and "age" of the donor also reduces regenerative functionality of MSCs and their clinical use for repair and regeneration of damaged and lost tissues [6]. It is pertinent to note that elderly population is the main portion of population for potential stem cell-based regenerative therapies. However, autologous use of cells from aged individuals seems not to provide the expected benefits of stem cell-based therapies due to age depleted function of stem cells from such patients [7]. It is therefore required to enhance the potential of stem cells before clinical use. Different strategies have been employed for this purpose such as growth factors preconditioning [8], mild heat shock [9], and glucose depletion [10].

Different pretreatment strategies have been employed to enhance the regenerative potential of stem cells, however; hypoxic preconditioning seems more effective for enhancing stem cell function because relatively low oxygen concentrations prevail in stem cells niches as compared to normoxic conditions. Hypoxia can be an effective strategy for enhancing the cells function because it can make the cells adapt external microenvironment, reduce oxidative stress, shift metabolism towards glycolysis, enhance proliferation, differentiation and maintain stemness, and improve their motility to tolerate the hypoxic preconditioning after transplantation [11].
