6. Safety concerns regarding the use of cell transplantation

Therapeutic approaches of cellular transplantation are revolutionizing the field of regenerative medicine; however, it also raises different safety concerns regarding several associated risk factors including tumorigenesis, adverse immunogenic response, transmission of extrinsic factors and differentiation into unwanted cellular progeny [127, 128].

### 6.1. Cyst/tumor formation

The intrinsic characteristics of ESCs and adult stem cells (ASCs) correlate to cancerous cells, for instance, their extended lifespan, comparative apoptotic resistance and potential to divide for longer time period [129]. Moreover, maintenance of required growth signals and other tightly regulated mechanisms can be observed in both cancerous and stem cells [130, 131]. Thus, the pluripotency of ESCs and multipotency of adult stem cells are regarded as the crucial aspect of developing tumors. The tumorigenic potential of cellular transplantation therapy could be intrinsic or adventitious, depending upon the microenvironment of transplanted cells [130]. It has been reported that following differentiation of stem cells into mature cells, the later can induce tumorigenesis due to acquiring several mutations in the process of parent-stem cells culture [132].

#### 6.2. Immune rejection

An immune rejection is another apparent safety concern that could escalate after cellular transplantation therapy. A transplanted cell could either directly prompt an immunogenic reaction or could have a regulatory influence on the immune system [133]. Several factors may impact the host-induced immunogenicity depending upon the location of cellular transplantation and number of administered doses [134]. MSCs and other ESC-derived progeny are being described as immunoprivileged and hold little immunogenicity [135]. It has been shown that MSCs can cause suppression of T cell to proliferate, prevent monocytes to differentiate [136] and can also hinder B cell to proliferate and/or differentiate [137]. In addition, extracts from both mouse and hESCs have been shown to maintain immune regulatory characteristics of ESCs [138].
