**1. Development of Radiation-Induced Lesions**

It is now well accepted that the human body contains adult stem cells or in other words post-natal stem cells that are capable of differentiating into other tissues and can regenerate or repair damaged tissues. Over the last decades, stem cell hypothesis, the development of tissue deficits due to the inability of stem cells to replenish lost cells, has become a reality. Stem cells were in a way studied by radiobiologists well before it was proposed as a hypothesis. In fact, the initial theory of the development of radiation lesions' "target cell theory" was based on radiation-induced cell loss. Target cell theory introduced by Puck and Marcus [1] considers cell loss as the cardinal cause of radiation induced normal tissue damage or tumour ablation. In recent years, it has been shown that the process of development of radiation damage and the damage itself starts by molecular changes long before denudation of target cells. However, one cannot deny the fact that the ultimate lesions manifest as loss of functional cells. Most bodily tissues possess a pool of clonogenic cells that are mobilised in response to assaults such as trauma or radiation. Damage to the tissue is repaired by proliferation of clonogenic or tissue specific stem cells. Sterilisation of these clonogenic cells by radiation manifests as radiation damage. In mild cases as the damage is sensed, these clonogenic cells migrate to the site of damage, and together with

**Citation:** Rezvani, M. Therapeutic Potential of Mesenchymal Stromal Cells and Extracellular Vesicles in the Treatment of Radiation Lesions—A Review. *Cells* **2021**, *10*, 427. https:// doi.org/10.3390/cells10020427

Academic Editors: Alain Chapel and Joni H. Ylostalo

Received: 11 November 2020 Accepted: 13 February 2021 Published: 18 February 2021

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local surviving clonogic cells, proliferate to repair the tissue. However, in severe cases of tissue repairs, there might not be enough surviving clonogenic cells as the site of damage or sufficient number of mobilised cells to reach the site and repair the damage. Thus, the damage gets established as a result of failure of endogenous stem cells to regenerate the damaged tissue.

In early responding tissues, such as gut, oral mucosa, or epidermis of skin, the initiation of molecular events triggered by radiation results in the loss of both clonogenic and differentiated functional cells. Loss of clonogenic cells or in other words basal stem cells results in a deficiency to replace the lost functional cells. In the event of survival of a sufficient number of proliferating tissue specific stem cells in the irradiated region or its vicinity, complete healing is observed. However, in severe cases, where the radiation causes sterilisation of the tissue-specific clonogeic cells, denudation of the tissue will follow. Deficiency of the stem cells to produce new cells to replace the lost cells and resulting imbalance brings about the erosion of the epithelial layer.

In late responding tissues, such as late dermal reaction of skin or central nervous system damage, the involvement of stem cells are also established. However, the pattern of development of lesions in late responding tissues is more complex, as the response of slow turnover tissues (such as neural tissue) differ from the response of rapid turnover tissues (such as epithelial tissue). In late responding tissues, the overall tissue response is dependent on more than one cell type and their response to irradiation. The complex process of late radiation damage is initiated by a cascade of molecular events from injured cells that result in eventual denudation of functional differentiated cells. The response develops as the consequence of damage to both slow and rapid turnover tissues. For example, a rapid unset of radiation-induced apoptosis has been reported as early as 3–6 h in dentate gyrus after irradiation of rat brain [2,3]. These authors also reported a higher number of apoptosis than the number of proliferating cells and concluded that non-proliferating cells as well as proliferating cells in the subgranular zone of rat brain were sensitive to radiation and cell number, in this region, was significantly lower than age-matched controls 120 days after irradiation. This in part can be the cause of radiation-induced cognitive deficit. A dosedependent reduction in the number of subepidermal cells in irradiated rat brain and the inability of surviving stem cells in regenerating the subepiderma, that manifest a clear deficit at 180 days after irradiation, was reported [2]. Deficiency of stem cells to regenerate the lost tissue results in the development of scaring or fibrosis as a final lesion. Therefore, the replacement of stem cells by donor stem cells, possibly before establishment of the lesion, may prevent the development or shorten the duration/severity of the lesions in both early and late responding tissues.
