**3. Types of Stem Cells**

Stem cells are undifferentiated cells that are capable of dividing to produce more stem cells and/or differentiate specialised cells. Stem cells are classified by their potentiality into three main types; multipotent, pluripotent, and totipotent. Totipotent stem cells can generate an entire individual. Pluripotency is the ability of certain cells to differentiate into the three embryonic layers (ectoderm, mesoderm, and endoderm). Multipotency is the ability of stem cells to differentiate into one or two embryonic layers such as mesoderm and endoderm. In contrast, adult stem cells are multipotent cells.The stem cells currently used in medical applications or studied in research can be divided into three main types.


in the maintenance of marrow microenvironment by secreting bioactive factors [23]. MSCs of adipose tissue are termed Adipose Tissue-derived Stem cells (ADSCs), which, like other MSCs are spindle-shaped plastic adherent cells, capable of differentiating to other cells [24,25]. Another source of MSCs (UC-MSCs) is umbilical cord blood [26] or Wharton jelly of umbilical cord [27,28]. UC-MSCs like other MSCs differentiate into three germ layers and contribute to tissue repair and regeneration [29].

ES and IPS cells have the advantage of indefinite renewal and the ability to differentiate into all cell types. This property gives them a role in replacing damaged cells by direct differentiation. On the other hand, adult stem cells are limited in their proliferation. Adult stem cells can either differentiate to replace specialized cells but in a limited number of cases. This is the case, for example, with MSCs that differentiate into osteoblasts. On the other hand, when adult stem cells come to repairing tissue from which they did not originate, they preferentially act by trophic effect, such as MSCs to allow intestinal regeneration.

The Mesenchymal and Tissue Stem Cell Committee of the International Society for Cellular Therapy [30] states three conditions as the minimal criteria for definition of human MSC. (1) MSC must be plastic-adherent, (2) express CD105, CD73, and CD90, and lack expression of CD45, CD34, CD14 or CD11b, CD79alpha or CD19 and HLA-DR surface molecules, and (3) differentiate into osteoblasts, adipocytes, and chondroblasts in vitro. MSCs has been shown to differentiate into endodermal lineage such as hepatocytes [31], cardiomyocytes [32], and ectodermal lineage neurons [33].

MSCs are the most extensively studied adult stem cells and BM-MSCs are the first to be transplanted and used in regenerative medicine, including treatment of radiation lesions. Alternatively, ADSCs appear to be a better kind of MSCs [34]. Furthermore, ADSCs can be obtained by lipoaspiration, which is much less invasive than obtaining BM-MSCs by bone marrow aspiration. ADSCs exhibit intermediate radiation sensitivity [35] and it appears that irradiation of human ADSCs with low-level laser changes their morphology and enhances their proliferation and therapeutic potential [36]. The potential of mesenchymal stem cell therapy in the treatment of radiation-induced lesions has been reviewed [37].

### **4. Homing of Transplanted Stem cells**

MSCs, for regenerative purposes, can be transplanted directly into the site of damage or introduced systemically. In the latter, it is assumed that homing of the transplanted cells is regulated by the local microenvironment and they are directed to the site of injury by cues from damaged tissues of the host through a series of signals. Furthermore, the transplanted cells secrete diverse trophic factors and immunomodulatory substances that contribute to the process of regeneration by stimulating the endogenic stem cells. In majority of the studies of the distribution of transplanted cells in irradiated animals, it has been shown that the transplanted cells home to the radiation-damaged tissues. MSCs intravenously transplanted to rats with myocardial lesions home to the infarct region of the heart, while in uninjured control animals, the transplanted cells migrated to the bone marrow [38]. In the treatment of radiation-induced multi-organ failure in non-human primates, transplanted MSCs home to injured tissues [39]. Human MSCs were systemically transplanted into total body or abdominal irradiated NOD/SCID mice [40,41]. It was reported that the transplanted cells home to the irradiated organs and were found three months post irradiation. These observations support the hypothesis that transplanted stem cells migrate to radiation-induced injury sites in irradiated animals. However, this does not seem to be specific to radiation lesions as migration of transplanted stem cells to non-radiation damaged tissues has been reported too. In an acute nontransmural myocardial infarct model [42], it was shown that transplanted MSCs mainly home to the infarct myocardial region observed 24 h after intravenous transplantation that lasted for 7 days after transplantation. However, these authors observed some migration to non-target organs as well but the main concentration was in the infarct region.

Homing factors are crucial in the delivery of stem cells to damaged tissues. Some homing factors have been identified. For example stromal cell-derived factor-1 (SDF-1) is known

6

to allow the targeting of hematopoietic stem cells to the marrow when it needs to be recolonized by hematopoietic stem cells. The secretion of SDF-1 similarly allows the homing of MSCs that express the C-X-C Motif Chemochine Receptor-4 (CXCR4) molecule, which is the receptor for the SDF-1 molecule. Another chemokine, Monocyte Chemotactic Protein-1 (MCP-1), was found to be a key regulator for stem cell recruitment to the myocardium in or cochlear tissue.

#### **5. Stem Cell Treatment of Radiation Lesions**

Interest in the application of mesenchymal cells as therapeutics has increased recently. A few early stage clinical trials have also been reported [43–46] but in general one can say that treatment with MSCs is still in an experimental phase and larger clinical trials are needed before its clinical use. Safety of MSCs in clinical trials have been reviewed and adverse effects listed [47]. The safety of MSCs for the treatment of radiation lesions has also been reported [48].

Like other cells, irradiation of MSCs induces senescence and/or apoptosis [49]. This has been shown in MSCs isolated from irradiated human skin, where colony formation, proliferation, and differentiation capacity are reduced [50].

MSCs have been shown not to give rise to tumours [51] as they are non-tumourgenic [52].
