In several clinical trials, MSCs expanded in vitro are being transplanted to find out their efficacy in treating degenerative diseases, reducing acute rejection of transplanted organs, and in preventing and treating graft-versus-host following website disease [25, 29�C32]. Sometimes the expanded cells are induced to differentiate into a particular cell type and then the predifferentiated cells are transplanted for the regeneration of particular tissues or organs [33]. After transplantation, tissue-specific migration and engraftment ensure the success of cell-based regenerative therapy. From isolation to engraftment, the MSCs usually pass through two different environmental conditions. One is the in vitro culture condition (from isolation to transplantation) and the other is the in vivo or physiological condition (before isolation and after transplantation) (Figure 1).

At present, most of the expansion procedures of MSCs are performed under ambient O2 concentration, where cells are exposed to 20% O2, which is approximately 4�C10 times more than the concentration of O2 in their natural niches [35, 36]. The higher O2 concentration might cause environmental stress to the in vitro cultured MSCs. Moreover, in recent years, several studies have presented clear evidence regarding the negative influence of ambient O2 concentration on MSCs, including early senescence, longer population doubling time, DNA damage [37, 38], and poor engraftment following transplantation [33, 39]. All these have shown the influential effect of O2 concentration on MSCs biology and raised serious concern over its therapeutic efficiency and biosafety.

Figure 1Steps involved in MSCs-based therapy.Numerous in vitro studies have been conducted in the last two decades to analyze the complex processes involved in stem cell maintenance. However, the role of physiologically normoxic (hypoxic) conditions (usually 2�C9% O2 concentration) on stem cell biology received very little attention [40]. Thus, this paper discusses the differences between in vitro MSC culture in ambient and hypoxic conditions. Finally this paper also highlights how MSCs cultured in vitro in hypoxic conditions can offer a solution for MSCs-based therapy. 2. Stem Cell NicheIn both in vitro and in vivo conditions, the fate and function of stem cells depend upon their intrinsic genetic program and the local microenvironment, often referred to as the ��stem cell niche�� [41]. The stem cell niche concept was proposed by Schofield Brefeldin_A in 1978 [42], and several researchers have tried to elucidate the confusion and controversy over it [43�C45].