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 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 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.
1. Treatment of Radiation Lesions with Stem Cells
Radiation lesions is amenable to treatment by methods that result in repairing or regeneration of the damaged tissue. In fact, stem cell transplantation in medical practice is not new and have been used for decades in bone marrow transplantation .
Stem cell treatment of radiation damage is based on the assumption that the transplanted cells integrate with the damaged host tissue to replace the damaged/lost cells or stimulate the host cells to prevent the damage or regenerate the damaged tissue. The later will obviously be more efficient before establishment of the radiation damage. Transplanting the stem cells before the full establishment of radiation lesion can prevent the development of radiation damage or shorten the duration of the manifestation of the lesion.
Bone marrow transplantation has been successfully used in the treatment of leukaemia, lymphoma, and certain types of anaemia procedures. Initial efforts in this field were directed towards transplantation of pre-differentiated stem cells and a good example of this is bone marrow transplantation that started as early as 1951 with the work of Lorenz  who found that infusion of the spleen or marrow cells could protect the irradiated mice. Bone marrow transplantation is based on allogenic use of stem cells. Whole marrow or stem cells of the marrow are extracted from a donor and transplanted to the host to reconstruct the haemopoietic tissues of cancer patients. The patient, prior to bone-marrow transplantation, is myeloablated by radiation or chemotherapy. The process of bone marrow transplantation is reviewed by .
Later, non-tissue specific or naive stem cells were transplanted on the basis of the opinion that the niche, or local microenvironment, consisting of surrounding cells, will define the fate of the transplanted cells and direct the administered stem cells to lodge into target tissue and differentiate into the required cells to restore structural and functional deficits.
In this article, a number of papers indicating the application of stem cells in the treatment of radiation-induced lesions are reviewed. It is also argued that the beneficial effect of transplanted stem cells in irradiated bodies is not necessarily due to the lodging of the transplanted stem cells in the irradiated tissue to replace the lost/damaged cells. It is suggested that perhaps the result is by paracrine effect; i.e., transplanted stem cells secrete bioactive substances that are capable of stimulating the host cells to reproduce and repair the damaged tissue. This means that the transplanted stem cells, besides integrating in the structure of damaged tissues, secrete biologically active factors, mainly in the form of extracellular vesicles, such as exosomes and microvesicles, that stimulate and mobilise the endogenous stem cells to repair the damage. Recently, it was shown by many researchers including ourselves, that the effect of stem cells is exerted in a paracrine fashion . Transplanted stem cells, by integration with the host tissue, mobilisation of endogenous stem cells, or a combination of both mechanisms, result in functional and structural improvements of injured tissues. For a review on extracellular vesicles, see .
2. 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.
(1) Embryonic stem cells (ES): these are pluripotent cells located at the inner cell mass of blastocysts. Embryonic stem cells are usually harvested around four days after fertilisation when the embryo is in its blastula phase . Embryonic stem cells can be differentiated into any one of the three germ layers; endoderm, mesoderm, or ectoderm.
(2) Induced pluripotent stem cells (iPCs): these cells, as indicated by their name are pluripotent that are generated from mature somatic cells, like skin or blood cells, by introduction of transcription factors for encoding certain genes. This is in fact back reprogramming of mature cells to embryonic stem cell state. The classic mixture of transcriptions factors to produce iPSCs consist of Oct3/4, Sox2, Klf4, and c-Myc .
(3) Adult stem cells: This is another group of stem cells that are multipotent. Adult stem cells or adult progenitor cells are tissue-specific stem cells are available almost in all body tissues such as epidermal stem cells of skin, stem cells of human hair follicles, cardiac stem cells of heart, neural stem cells of the brain, hepatic stem cells, intestinal stem cells, dental pulp stem cells, ovarian epithelial stem cells, mammary stem cells, testicular stem cells, and satellite cells/myogenic stem cells of the skeletal muscle. Hemopoietic stem cells and mesenchymal stem cells are other groups of adult stem cells. Hemopoietic stem cells are derived from blood vessels and bone marrow. Mesenchymal stromal cells (MSCs) are another type of multipoint adult cells  found in bone marrow, adipose tissue, and almost all postnatal tissues. MSCs are non-hematopoietic stem cell-like cells first identified by Friedenstein  and their characteristics are described . In bone marrow, MSCs have a supportive role for hematopoietic stem progenitor cells (HSPCs) that is also involved in the maintenance of marrow microenvironment by secreting bioactive factors . 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 . Another source of MSCs (UC-MSCs) is umbilical cord blood or Wharton jelly of umbilical cord . UC-MSCs like other MSCs differentiate into three germ layers and contribute to tissue repair and regeneration .
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 Therapystates 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 , cardiomyocytes , and ectodermal lineage neurons.
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. 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 and it appears that irradiation of human ADSCs with low-level laser changes their morphology and enhances their proliferation and therapeutic potential . The potential of mesenchymal stem cell therapy in the treatment of radiation-induced lesions has been reviewed.
3. 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 . In the treatment of radiation-induced multi-organ failure in non-human primates, transplanted MSCs home to injured tissues . Human MSCs were systemically transplanted into total body or abdominal irradiated NOD/SCID mice . 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 , 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 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.
4. 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  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 . The safety of MSCs for the treatment of radiation lesions has also been reported.
Like other cells, irradiation of MSCs induces senescence and/or apoptosis . This has been shown in MSCs isolated from irradiated human skin, where colony formation, proliferation, and differentiation capacity are reduced.
5. Studies on Hematopoietic System
Although interest in stem cell treatment increased over the last two decades, stem cell transplantation started more than half a century ago with bone marrow transplantation by Lorenz et al. followed by Barnes et al. . These authors demonstrated that transplantation of bone marrow cells could protect mice against ionising radiation. This was the pioneering process of bone marrow transplantation that developed as a routine clinical procedure, where whole marrow or marrow cells extracted from bone marrow are transplanted into myeloablated host in the treatment of both malignant and non-malignant diseases such as leukaemia, lymphoma, and certain types of anaemia .
The effect of transplantation of bone marrow-derived mononuclear cells in non-human primates were studied by Bertho et al. . These authors demonstrated that cell transplantation 24 h after 8 Gy total body irradiation shortened the period and severity of pancytopenia. Acute radiation syndrome (ARS), besides multi-organ failure, causes pancytopenia too. The efficacy of transplantation of human UC-MSCs to combat the effects of ARS was also studied . However, in this study, UC-MSCs were modified to to express human extracellular superoxide dismutase. The regenerative potential of MSCs combined with the antioxidant effect of human extracellular superoxide dismutase was intended to produce a rapid and effective strategy for the treatment of radiation accident victims.
The protective effects of allogenic stem cell transplantation against acute radiation syndrome was demonstrated by transplantation of human umbilical cord-derived MSCs in mice .
The entry is from 10.3390/cells10020427
- Thomas, E.D. A history of haemopoietic cell transplantation. Br. J. Haematol. 1999, 105, 330–339.
- Lorenz, E.; Uphoff, D.; Reid, T.R.; Shelton, E. Modification of irradiation injury in mice and guinea pigs by bone marrow in-jections. J. Natl. Cancer Inst. 1951, 12, 197–201.
- Collino, F.; Deregibus, M.C.; Bruno, S.; Sterpone, L.; Aghemo, G.; Viltono, L.; Tetta, C.; Camussi, G. Microvesicles derived from adult human bone .;marrow and tissue specific mesenchymal stem cells shuttle selected pattern of miRNAs. PLoS ONE. 2010, 5, e11803.
- Camussi, G.; Deregibus, M.C.; Cantaluppi V. Role of stem-cell-derived microvesicles in the paracrine action of stem cells. Biochem. Soc. Trans. 2013, 41, 283–287.
- Anger, F.; Camara, M.; Ellinger, E.; Germer, C.T.; Schlegel, N.; Otto C.; Klein, I. Human Mesenchymal Stromal Cell-Derived Extracellular Vesicles Improve Liver Regeneration After Ischemia Reperfusion Injury in Mice. Stem Cells Dev. 2019, 28, 1451–62.
- National Toxicology Program. Final Report on Carcinogens Background Document for Formaldehyde. Rep Carcinog Backgr Doc. 2010, (10-5981):i-512.
- Zha, Q.B.; Yao, Y.F.; Ren, Z.J.; Li, X.J.; Tang, J.H. Extracellular vesicles: An overview of biogenesis, function, and role in breast cancer. Tumour Biol. 2017, 39, doi.org/10.1177/1010428317691182
- Thomson, J.A.; Itskovitz-Eldor, J.; Shapiro, S.S.; Waknitz, M.A.; Swiergiel, J.J.; Marshall, V.S.; Jones, J.M. Embryonic stem cell lines derived from human blastocysts. Science. 1998, 282, 1145–7.
- Yamanaka S. Strategies and new developments in the generation of patient-specific pluripotent stem cells. Cell stem cell. 2007, 1, 39–49.
- Rogers, E.H.; Hunt, J.A.; Pekovic-Vaughan, V. Adult stem cell maintenance and tissue regeneration around the clock: Do impaired stem cell clocks drive age-associated tissue degeneration? Biogerontology. 2018, 19, 497–517.
- Caplan, A.I. Mesenchymal stem cells. Journal of orthopaedic research : Official publication of the Orthopaedic Research Society. 1991, 9, 641–650.
- Pittenger, M.F.; Mackay, A.M.; Beck, S.C.; Jaiswal, R.K.; Douglas, R.; Mosca, J.D.; Moorman, M.A.; Simonetti, D.W.; Craig, S.; Marshak, D.R. Multilineage potential of adult human mesenchymal stem cells. Science. 1999, 284, 143–147.
- Keating, A. Mesenchymal stromal cells. Current opinion in hematology. 2006, 13, 419–425.
- Zuk, P.A.; Zhu, M.I.N.; Mizuno, H.; Huang, J.; Futrell, J.W.; Katz, A.J.;; Benhaim, P.; Lorenz, H.P.; Hedrick, M.H. Multilineage cells from human adipose tissue: Implications for cell-based therapies. Tissue Eng. 2001, 7, 211–28.
- Zuk, P.A.; Zhu, M.; Ashjian, P.; De Ugarte, D.A.; Huang, J.I.; Mizuno, H.; Alfonso, Z.C.; Fraser, J.K.; Benhaim, P.; Hedrick, M.H. Human adipose tissue is a source of multipotent stem cells. Mol. Biol. Cell. 2002, 13, 4279–95.
- Hennrick, K.T.; Keeton, A.G.; Nanua, S.; Kijek, T.G.; Goldsmith, A.M.; Sajjan, U.S.; Bentley, J.K.; Lama, V.N.; Moore, B.B.; Schumacher, R.E.; Thannickal, V.J. Lung cells from neonates show a mesenchymal stem cell phenotype. American journal of respiratory and critical care medicine. 2007, 175, 1158–64.
- Friedenstein, A.J.; Deriglasova, U.F.; Kulagina, N.N.; Panasuk, A.F.; Rudakowa, S.F.; A Luriá, E.; A Ruadkow, I. Precursors for fibroblasts in different populations of hematopoietic cells as detected by the in vitro colony assay method. Exp. Hematol. 1974, 2, 83–92.
- Friedenstein, A.J. Precursor cells of mechanocytes. International review of cytology. 1976, 47, 327–59.
- Li, Z.; Hu, X.; Zhong, J.F. Mesenchymal Stem Cells: Characteristics, Function, and Application. Stem cells international. 2019, 2019, 8106818.
- Crippa, S.; Bernardo, M.E. Mesenchymal Stromal Cells: Role in the BM Niche and in the Support of Hematopoietic Stem Cell Transplantation. Hemasphere. 2018, 2, e151.
- Casteilla, L.; Planat-Benard, V.; Laharrague, P.; Cousin, B. Adipose-derived stromal cells: Their identity and uses in clinical trials, an update. World J. Stem Cells. 2011, 3, 25–33.
- Baer, P.C.; Koch, B.; Hickmann, E.; Schubert, R.; Cinatl, J.J.; Hauser, I.A.; Geiger, H. Isolation, Characterization, Differentiation and Immunomodulatory Capacity of Mesenchymal Stromal/Stem Cells from Human Perirenal Adipose Tissue. Cells 2019, 8, 1346, doi:10.3390/cells8111346.
- Amati, E.; Sella, S.; Perbellini, O.; Alghisi, A.; Bernardi, M.; Chieregato, K.; Lievore, C.; Peserico, D.; Rigno, M.; Zilio, A.; et al. Generation of mesenchymal stromal cells from cord blood: evaluation of in vitro quality parameters prior to clinical use. Stem Cell Res. Ther. 2017, 8, 1–15, doi:10.1186/s13287-016-0465-2.
- Wang, H.S.; Hung, S.C.; Peng, S.T.; Huang, C.C.; Wei, H.M.; Guo, Y.J.; Fu, Y.S.; Lai, M.C.; Chen, C.C. Mesenchymal stem cells in the Wharton’s jelly of the human umbilical cord. Stem Cells. 2004, 22, 1330–1337.
- Friedman, R.; Betancur, M.; Boissel, L.; Tuncer, H.; Cetrulo, C.; Klingemann, H. Umbilical cord mesenchymal stem cells: Ad-juvants for human cell transplantation. Biol. Blood Marrow Transplant. 2007, 13, 1477–1486.
- Nagamura-Inoue, T.; He, H. Umbilical cord-derived mesenchymal stem cells: Their advantages and potential clinical utility. World J. Stem Cells. 2014, 6, 195–202.
- Dominici, M.; Le Blanc, K.; Mueller, I.; Slaper-Cortenbach, I.; Marini, F.; Krause, D.; Deans, R.J.; Keating, A.; Prockop, D.J.; Horwitz, E.M.; et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006, 8, 315–317.
- Lange, C.; Bassler, P.; Lioznov, M.V.; Bruns, H.; Kluth, D.; Zander, A.R.; Fiegel, H.C. Liver-specific gene expression in mes-enchymal stem cells is induced by liver cells. World J. Gastroenterol. 2005, 11, 4497–4504, doi:10.3748/wjg.v11.i29.4497.
- Toma, C.; Pittenger, M.F.; Cahill, K.S.; Byrne, B.J.; Kessler, P.D. Human mesenchymal stem cells differentiate to a cardiomyocyte phenotype in the adult murine heart. Circulation. 2002, 105, 93–98.
- Takeda, Y.S.; Xu, Q. Neuronal Differentiation of Human Mesenchymal Stem Cells Using Exosomes Derived from Differenti-ating Neuronal Cells. PLoS ONE. 2015, 10, e0135111.
- Zhu, Y.; Liu, T.; Song, K.; Fan, X.; Ma, X.; Cui, Z. Adipose-derived stem cell: A better stem cell than BMSC. Cell Biochem. Funct. 2008, 26, 664–675.
- Baasse, A.; Machoy, F.; Juerss, D.; Baake, J.; Stang, F.; Reimer, T.; Krapohl, B.D.; Hildebrandt, G. Radiation Sensitivity of Ad-ipose-Derived Stem Cells Isolated from Breast Tissue. Int. J. Mol. Sci. 2018, 19, 1988, doi:10.3390/ijms19071988..
- Nurković, J.; Zaletel, I.; Nurković, S.; Hajrović, Šefćet; Mustafić, F.; Isma, J.; Škevin, A.J.; Grbović, V.; Filipović, M.K.; Dolićanin, Z. Combined effects of electromagnetic field and low-level laser increase proliferation and alter the morphology of human adipose tissue-derived mesenchymal stem cells. Lasers Med Sci. 2016, 32, 151–160, doi:10.1007/s10103-016-2097-2.
- Nicolay, N.H.; Lopez Perez, R.; Debus, J.; Huber, P.E. Mesenchymal stem cells — A new hope for radiotherapy-induced tissue damage? Cancer letters. 2015, 366, 133–140.
- Saito, T.; Kuang, J.Q.; Bittira, B.; Al-Khaldi, A.; Chiu, R.C. Xenotransplant cardiac chimera: Immune tolerance of adult stem cells. The Annals of thoracic surgery. 2002, 74, 19–24.
- Chapel, A.; Bertho, J.M.; Bensidhoum, M.; Fouillard, L.; Young, R.G.; Frick, J.; Demarquay, C.; Cuvelier, F.; Mathieu, E.; Trompier, F.; et al. Mesenchymal stem cells home to injured tissues when co-infused with hematopoietic cells to treat a radia-tion-induced multi-organ failure syndrome. The journal of gene medicine. 2003, 5, 1028–1038.
- François, S.; Bensidhoum, M.; Mouiseddine, M.; Mazurier, C.; Allenet, B.; Semont, A.; Frick, J.; Saché, A.; Bouchet, S.; Thierry, D.; et al. Local Irradiation Not Only Induces Homing of Human Mesenchymal Stem Cells at Exposed Sites but Promotes Their Widespread Engraftment to Multiple Organs: A Study of Their Quantitative Distribution After Irradiation Damage. STEM CELLS 2006, 24, 1020–1029, doi:10.1634/stemcells.2005-0260.
- Mouiseddine, M.; Francois, S.; Semont, A.; Sache, A.; Allenet, B;. Mathieu, N.; Frick, J.; Thierry, D.; Chapel, A. Human mes-enchymal stem cells home specifically to radiation-injured tissues in a non-obese diabetes/severe combined immunodeficiency mouse model. Br. J. Radiol. 2007, 80, doi.org/10.1259/bjr/25927054.
- Kraitchman, D.L.; Tatsumi, M.; Gilson, W.D.; Ishimori, T.; Kedziorek, D.; Walczak, P.; Segars, W.P.; Chen, H.H.; Fritzges, D.; Izbudak, I.; Young, R.G.; et al. Dynamic imaging of allogeneic mesenchymal stem cells trafficking to myocardial infarction. Circulation. 2005, 112, 1451–1461.
- Golpanian, S.; Difede, D.L.; Khan, A.; Schulman, I.H.; Landin, A.M.; A Tompkins, B.; Heldman, A.W.; Miki, R.; Goldstein, B.J.; Mushtaq, M.; et al. Allogeneic Human Mesenchymal Stem Cell Infusions for Aging Frailty. Journals Gerontol. Ser. A: Boil. Sci. Med Sci. 2017, 72, 1505–1512, doi:10.1093/gerona/glx056.
- Pang, Y.; Xiao, H.W.; Zhang, H.; Liu, Z.H.; Li, L.; Gao, Y.; Li, H.B.; Jiang, Z.J.; Tan, H.; Lin, J.R.; ; Du, X.; et al. Allogeneic Bone Marrow-Derived Mesenchymal Stromal Cells Expanded In Vitro for Treatment of Aplastic Anemia: A Multicenter Phase II Trial. Stem Cells Transl Med. 2017, 6, 1569–1575.
- Tompkins, B.A.; DiFede, D.L.; Khan, A.; Landin, A.M.; Schulman, I.H.; Pujol, M.V.; Heldman, A.W.; Miki, R.; Gold-schmidt-Clermont, P.J.; Goldstein, B.J.; Mushtaq, M.; et al. Allogeneic Mesenchymal Stem Cells Ameliorate Aging Frailty: A Phase II Randomized, Double-Blind, Placebo-Controlled Clinical Trial. J. Gerontol. A Biol. Sci. Med. Sci. 2017, 72, 1513–22.
- Jo, C.H.; Chai, J.W.; Jeong, E.C.; Oh, S.; Kim, P.S.; Yoon, J.Y.; Yoon, K.S. Intratendinous Injection of Autologous Adipose Tis-sue-Derived Mesenchymal Stem Cells for the Treatment of Rotator Cuff Disease: A First-In-Human Trial. STEM CELLS 2018, 36, 1441–1450, doi:10.1002/stem.2855.
- Toyserkani, N.M.; Jørgensen, M.G.; Tabatabaeifar, S.; Jensen, C.H.; Sheikh, S.P.; Sørensen, J.A. Concise Review: A Safety As-sessment of Adipose-Derived Cell Therapy in Clinical Trials: A Systematic Review of Reported Adverse Events. STEM CELLS Transl. Med. 2017, 6, 1786–1794, doi:10.1002/sctm.17-0031.
- Grønhøj, C.; Jensen, D.H.; Vester-Glowinski, P.; Jensen, S.B.; Bardow, A.; Oliveri, R.S.; Fog, L.M.; Specht, L.; Thomsen, C.; Darkner, S.; et al. Safety and Efficacy of Mesenchymal Stem Cells for Radiation-Induced Xerostomia: A Randomized, Place-bo-Controlled Phase 1/2 Trial (MESRIX). Int. J. Radiat. Oncol. 2018, 101, 581–592, doi:10.1016/j.ijrobp.2018.02.034.
- Alessio, N.; Del Gaudio, S.; Capasso, S.; Di Bernardo, G.; Cappabianca, S.; Cipollaro, M.; Peluso, G.; Galderisi U. Low dose radiation induced senescence of human mesenchymal stromal cells and impaired the autophagy process. Oncotarget. 2015, 6, 8155–8166.
- Johnson, M.B.; Niknam‐Bienia, S.; Soundararajan, V.; Pang, B.; Jung, E.; Gardner, D.J.; Xu, X.; Park, S.Y.; Wang, C.; Chen, X.; et al. Mesenchymal Stromal Cells Isolated from Irradiated Human Skin Have Diminished Capacity for Proliferation, Differenti-ation, Colony Formation, and Paracrine Stimulation. STEM CELLS Transl. Med. 2019, 8, 925–934, doi:10.1002/sctm.18-0112.
- Ra, J.C.; Shin, I.S.; Kim, S.H.; Kang, S.K.; Kang, B.C.; Lee, H.Y.; Kim, Y.J.; Jo, J.Y.; Yoon, E.J.; Choi, H.J.; et al. Safety of Intra-venous Infusion of Human Adipose Tissue-Derived Mesenchymal Stem Cells in Animals and Humans. Stem Cells Dev. 2011, 20, 1297–1308, doi:10.1089/scd.2010.0466.
- Ogura, F.; Wakao, S., Kuroda, Y.; Tsuchiyama, K.; Bagheri, M.; Heneidi, S.; Chazenbalk, G.; Aiba, S.; Dezawa, M. Human adipose tissue possesses a unique population of pluripotent stem cells with nontumorigenic and low telomerase activities: Po-tential implications in regenerative medicine. Stem Cells Dev. 2014, 23, 717–28.
- Barnes, D.W.; Corp, M.J.; Loutit, J.F.; Neal, F.E. Treatment of murine leukaemia with X rays and homologous bone marrow; preliminary communication. British medical journal. 1956, 2, 626–627.
- Friedrichs B, Tichelli A, Bacigalupo A, Russell NH, Ruutu T, Shapira MY; et al. Long-term outcome and late effects in patients transplanted with mobilised blood or bone marrow: A randomised trial. Lancet Oncol. 2010, 11, 331–8.
- Bertho, J.-M.; Frick, J.; Demarquay, C.; Lauby, A.; Mathieu, E.; Dudoignon, N.; Jacquet, N.; Trompier, F.; Chapel, A.; Joubert, C.; et al. Reinjection of Ex Vivo–Expanded Primate Bone Marrow Mononuclear Cells Strongly Reduces Radiation-Induced Aplasia. J. Hematotherapy 2002, 11, 549–564, doi:10.1089/15258160260091013.
- Gan, J.; Meng, F.; Zhou, X.; Li, C.; He, Y.; Zeng, X.; Jiang, X.; Liu, J.; Zeng, G.; Tang Y.; et al. Hematopoietic recovery of acute radiation syndrome by human superoxide dismutase-expressing umbilical cord mesenchymal stromal cells. Cytotherapy. 2015, 17, 403–417.
- Bandekar, M.; Maurya, D.K.; Sharma, D.; Checker, R.; Gota, V.; Mishra, N.; Sandur, S.K. Xenogeneic transplantation of human WJ‐MSCs rescues mice from acute radiation syndrome via Nrf‐2‐dependent regeneration of damaged tissues. Arab. Archaeol. Epigr. 2020, 20, 2044–2057, doi:10.1111/ajt.15819.