Skip to main content
PMC home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2017 Aug 1.
Published in final edited form as: Health Phys. 2016 Aug;111(2):198–203. doi: 10.1097/HP.0000000000000459

ADULT MESENCHYMAL STEM CELLS AND RADIATION INJURY

Juliann G Kiang 1
PMCID: PMC4929992  NIHMSID: NIHMS734592  PMID: 27356065

Abstract

Recent understanding in the cellular and molecular signaling activations on adult mesenchymal stem cells have provided new insights into their potential clinical applications, particularly for tissue repair and regeneration. This review focuses on these advances, specifically in the context of self-renewal for tissue repair and recovery after radiation injury. Thus far, MSCs have been extensively characterized and shown mitigation and therapy on acute radiation syndrome and cognitive dysfunction. Use of MSCs for treating radiation injury alone or in combination with additional trauma is foreseeable.

Keywords: stem cell, survival, repair, radiation, wound, bacteria, therapy

INTRODUCTION

Mesenchymal stromal cells (MSCs), also referred to as mesenchymal stem cells, have been attracting attention for different applications, including tissue engineering and regeneration on cell-based therapies (Kolf et al. 2007). They have been isolated from bone marrow and fat tissues. MSCs are characterized by fibroblast-like morphology, high proliferation rate, attachment to cell culture dishes and form colonies, and the capacity to differentiate into different mesenchymal lineages. They have been applied clinically to control autoimmune and graft-versus-host diseases (Chamberlain et al. 2007; Le Blanc et al. 2008; Tian et al. 2008; Djouad et al. 2009). In pre-clinical studies, MSC have been shown to provide protection against radiation-induced liver injury (Francois et al. 2013), promote healing in irradiated murine skin wounds (Hao et al. 2009; Kiang and Gorbunov, 2014), improve survival in irradiated mice (Hu et al. 2010), mitigate the gastrointestinal syndrome in mice (Saha et al. 2011), and restore the intestinal mucosal barrier in irradiated mice (Garg et al. 2014). Abdel-Mageed et al. (2009) reported that superoxide dismutase (SOD) gene-transfected MSCs improved survival in irradiated mice. However, other reports showed that MSCs alone did not improve survival in irradiated mice (Abdel-Mageed et al. 2009; Kiang and Gorbunov, 2014).

MSC CHARACTERIZATION

MSC Negative Markers

Friedenstein and colleagues identified MSCs as colony-forming unit-fibroblasts (CFU-Fs) in 1970, and Pittenger and colleagues described in detail the tri-lineage potential of MSCs in 1999. Our understanding of these cells has greatly moved forward since then. MSCs are multi-potent, adherent, and can be isolated from many adult tissue types. To ensure the isolated cells are MSCs, there is a consensus (Kolf et al. 2007) that MSCs do not express glycophorin-A (an erythroid linerage marker), cluster of differentiation (CD) 11b (an immune cell marker), CD31 (an endothelial and hematopoietic cell maker), CD34 (a primitive hematopoietic stem cell marker), CD45 (a marker of all hematopoietic cells), and CD117 (a hematopoietic stem/progenitor cell marker).

CD11b, CD34, CD45, and CD117 are certain MSC negative markers in both human MSCs and murine MSCs, while CD34 surface marker is certainly negative in human MSCs. In contrast, CD34 has also been found to be positive in murine MSCs (Kolf et al., 2007). Because of this uncertainty of markers in murine MSCs, multiple negative and positive surface markers are used for MSCs verification.

MSC Positive Markers

To ensure that isolated cells are MSCs, MSC positive markers are available. There are Stro-1, CD13, CD29, CD44, CD73, CD105, and CD106/vascular cell adhesion molecule-1 (VCAM-1) in human MSCs and murine MSCs. However, stem cells antigen-1 (Sca-1), CD10, CD90/thymocyte antigen 1 (Thy-1), and CD309/ fetal liver kinase 1 (Flk-1) are variable in both human MSCs and murine MSCs (Kolf et al., 2007). Therefore, it is important to characterize MSCs with more than one positive markers and negative markers. Stro-1 is the best-known MSC marker by far, because Stro-1 negative cells do not form colonies (Simmons et al. 1991). However, its expression in MSCs is gradually lost during culture expansion (Gronthos et al. 2003), with yet unidentified mechanism(s). It is unclear whether the loss of stro-1 marker will result in the loss of colony capability. Nevertheless, MSCs are always identified with Stro-1 in conjunction with other MSC positive and negative marker proteins.

Abdel-Mageed et al. (2009) identified MSCs with positive expression of CD13, CD29, CD44, CD105 and Sca-1 and negative expression of Thy-1.2, CD117/c-kit, CD11b, CD19, CD31, CD34, CD45, CD73, and CD135, while Francois et al. (2013) identified MSCs with positive expression of CD105 and CD73 and negative expression of CD45. Saha et al. (2011) identified MSCs with positive expression of CD29 and CD105 and negative expression of CD11b and CD133. Felka et al. (2014) identified MSCs with positive marker proteins CD73, CD90, CD105, and CD146, and negative marker proteins CD11b, CD14, CD34, and CD45.

The markers reported in the above publications to characterize MSCs are varied. But most of them showed at least 2 positive markers along with 2 negative markers to ensure MSCs. It should be even more credible by including CFU-Fs. In our laboratory, MSCs are identified with positive expression of Strol-1, Sca-1, CD44, and CD105 and negative expression of CD3 and CD34. MSCs are indeed further confirmed with colony formation (Kiang and Gorbunov, 2014). The combination we used to verify isolated MSCs and their expansion warrants correct identity of these cells.

MSC Self-Renewal and Maintenance

MSCs maintain their capability of self-renewal without differentiation. They express the embryonic stem cell gene markers octamer-binding transcription factor-4 (oct-4), sex determining region Y-box-2 (sox-2), and reduced expression protein-1 (rex-1, Izadpanah et al. 2006) that are involved in maintaining the repression of differentiation genes (Boyer et al. 2006). Additionally, the presence of leukemia inhibitory factor (LIF, Jiang et al. 2002; Metcalf 2003), fibroblast growth factor (FGF, Tsutsurri et al. 2001; Zaragosi et al. 2006), and mammalian homologues of drosophila wingless (Wnts, Kleber and Sommer, 2004; Boland et al. 2004) is detected. Hepatocyte growth factor (HGF), epidermal growth factor (EGF), platelet-derived growth factor (PDGF), and/or cytokines support MSC stemness in an MSC niche (Kolf et al. 2007). Beta-catenin, an extracellular matrix protein for anchoring cells in place is thought to be involved in Wnt regulation of MSC self-renewal (Bienz 2002). It takes 32–35 h (De Luca et al. 2013; Kiang and Gorbunov, 2014) to double MSC numbers.

The molecular mechanisms underlying MSC differentiation remain unclear. As for tissue repair and regeneration, MSC differentiation needs to be induced clinically by administration of transforming growth factor-beta (TGF-beta), bone morphogenetic protein (BMF), growth and differentiation factor (GDF, Chen et al., 2004), and Wnt ligands (Hartmann, 2006) for chondrogenesis, tenogenesis, and osteogenesis, peroxisome proliferator-activated receptor gamma (PPARgamma) for adipogenesis (Nuttal and Gimble 2004), and Notch 1 for myogenesis (Dezawa et al. 2005), respectively. The differentiation signal must find its way to the MSC niche for initiation of differentiation (Kolf et al. 2007).

MSCs AND THERAPY

MSCs and Radiation-induced damage in intestinal mucosal barrier

Radiation is known to induce intestinal damage. Garg and colleagues (2014) reported that male CD2F1 mice were subjected to a dose of 8 Gy total body irradiation (Cs-137 irradiator, 1.35 Gy min−1). Within 4–6 h after irradiation these mice received an intravenous injection of 2×107 bone marrow cells (BMCs) supplemented with 1×107 spleen cells. The transplantation accelerated peripheral blood counts, enhanced the recovery of intestinal immune cell populations in jejunum mucosa, reduced intestinal permeability, reduced interleukin-1 α (IL-1α) increases, restored IL-6, IL-10, and IL-12 concentrations, and modulated the expression of Claudin-2 and -4 (tight junction proteins). Since whole bone marrow preparation was injected, whether MSCs were responsible for mitigation of intestinal mucosal barrier damage remains unclear and needs to be further studied. Whole bone marrow transplantation also showed the significant survival improvement in female B6D2F1 mice after irradiation (Ledney and Elliott, 2010).

Saha and colleagues (2011) reported that male C57BL/6 mice were irradiated at 10 Gy (total body irradiation) or 16–20 Gy (abdominal irradiation) with a 320 KvP, Phillips MGC-40 orthovoltage irradiator (0.72 Gy min−1). These mice were then intravenously injected with 2×106 MSCs per mouse at 24 and 72 h after irradiation. All MSC administered mice survived from 10 Gy or 16–20 Gy for more than 25 days whereas irradiated mice administered with either the enriched myeloid fraction or the non-myeloid factions failed to improve survival. MSCs induced crypt interstitial stem cell (ISC) regeneration, restitution of the ISC niche, and xylose absorption. R-Spondin1, keratinocyte growth factor (KGF), PDGF, FGF2, and anti-inflammatory cytokines such as granulocyte-colony stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) were elevated in serum, while inflammatory cytokines (IL-6, IL-10, IL-12, and IL-17) declined.

MSCs and radiation-induced liver injury

Radiation induces liver injury that can be detected by elevation of aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Francois and colleagues (2013) reported that NOD/SCID mice were irradiated with Cs-137 at 3.2 Gy (1.85 Gy min−1) and then intravenously administered with 5×106 human MSCs in 0.1 mL 1× phosphate buffered saline. They indicated that MSC administration alone did not produce liver toxicity. MSC transplantation restored plasma urea, reduced plasma AST and ALT, and decreased the oxidative stress indicated by malondialdehyde (MDA) formation.

It has been reported that stromal cell-derived factor 1 (SDF1) secreted by cells within injured tissues and its receptor C-X-C chemokine receptor type 4 (CXCR4) were necessary for the MSC migrating to damaged tissues. Livers of MSC administered mice displayed high levels of SDF1 and CXCR4 with reduction of mir-27b after irradiation. The latter is known to down-regulate SDF1. It took 15 days for MSCs to differentiate into the hepatocyte phenotype as indicated by measuring liver specific genes such as cytokeratin 18 (CK18), CK19, and alpha-fetoprotein (AFP, Francois et al. 2013). Mir-27a has been shown to regulate genes for nuclear factor-keppa B (NF-keppaB) expression and hypoxia inducible factor-1alpha (HIF-1alpha) expression (Kiang et al., 2015).

MSCs and radiation-induced delay in wound healing

It is evident that radiation delays skin wound healing (Hao et al. 2009, Kiang et al. 2012). Hao et al. (2009) report that male Sprague-Dawley rats were exposed to 6 Gy of 60Co gamma-ray (0.31 Gy min−1) followed by a full-thickness excisional skin-wound (2% total body surface area). Then 1×107 recombinant adenovirus Adv-hPDGF-A/hBD2-GFP-infected MSCs (T-MSCs) or non-transfected MSCs (N-MSCs) were injected into the wound bed and margin of the excisional wound. These authors indicated that wounds in non-irradiated rats and irradiated rats took 17–18 days and 27–28 days, respectively, to heal. T-MSC administration and N-MSC administration was associated with a shorter healing time of 21 days and 24–25 days, respectively. MSCs promoted the deposition and remodeling of collagen in wounds. Significantly less bacterial colony formation was found in the cultured under-scar samples from the T-MSC administered wound bed. In our laboratory, when female B6D2F1 mice were exposed to 9.25 Gy of 60Co gamma-ray (0.4 Gy min−1) followed by a full-thickness excisional skin-wound (15 % total body surface area), MSCs (3×106) were intravenously injected 24 h after irradiation. Their wounds were fully closed by day 21 after irradiation, whereas wounds in vehicle-treated irradiated mice were not fully healed yet at this time. Our results are in agreement with observations reported by other laboratories (Hao et al. 2009). Wound healing is always a big issue after irradiation. The effectiveness of MSCs administration seems very promising for future clinical uses to shorten the healing process, improve patients’ hospitalization time and life quality, and reduce medical costs.

The benefit of MSCs can be a crucial factor in large animals as in small animals. Riccobono et al. (2012) reported that minipigs were locally irradiated at a dose of 50 Gy (60Co gamma-ray) and wound healing was measured. These authors found that autologous adipocyte-derived MSCs improved cutaneous radiation syndrome wound healing, whereas allogeneic adipocyte-derived stem cells did not. In small animals, MSCs collected from different individuals seem not to be an issue (Nemeth et al. 2009).

MSCs and radiation-induced cognitive dysfunction

Radiotherapy frequently leads to progressive and long-lasting declines in cognition that can severely impact quality of life (Aayomi, 1997; Butler et al., 2006; Meyers and Brown, 2006). Recent publications have demonstrated that administration of MSCs restores neuronal plasticity after irradiation. Acharya and the colleagues (2015) reported that radiation on brain resulted in cognate dysfunction. When total 4×105 human neural stem cells (hNSC) were injected into 4 different sites of hippocampus 1 month after 10 Gy at 2.07 Gy/min to the brain of immunodeficient male athymic nude rats, the hNSC transplantation promoted the long-term recovery of host hippocampal neurons and ameliorated cognitive dysfunction. The results are stunning and provide insights to further advance research in neuronal injury due to irradiation.

MSCs and radiation as well as bacterial challenge

MSCs normally have relative high amounts of constitutively expressed HSP70 and NF-keppaB-p65, and a detectable amount of NAD+-dependent deacetylase sirtuin-3 (Sirt3). Significant increases in heat shock protein 70kDa (HSP70), NF-keppaB-p65, Sirt3, and matrix metalloproteinase-3 (MMP3) were found, when MSCs were exposed to 12 Gy but not 8 Gy. Sirt3 is a mitochondrial stress-response protein. Increases in Sirt3 expression suggest that radiation induces stress to mitochondria. Caspase-3, a marker for caspase-dependent apoptosis, was not detected in irradiated MSCs, suggesting that no apoptosis takes place in MSCs after irradiation. Radiation induced significant increases in light chain 3 (LC3) expression, a marker of autophagy, detected by Western blotting and LC3-containing autophagy vacuoles displayed by immunofluorescent staining, suggesting presence of up-regulation of autophagy defense machinery.

It has been demonstrated that radiation induces systemic bacterial infection (Kiang et al. 2010; Fukumoto et al. 2013). In bone marrow, the immune homeostasis and defense response to blood pathogens are mediated by the marrow-blood barrier, which consists of endothelial, reticuloendothelial and mesenchymal stromal cell lineages (Balduino et al. 2005; Greenberger and Epperly, 2009; Krebsbach et al. 1999; Owen and Friedenstein, 1988). When MSCs were exposed to radiation or in combination with Gram-negative E. coli challenge (5×107 bacteria/ml), increases in lysosomal-associated membrane protein 1 (Lamp1), small ubiquitin-related modifier 1 (SUMO1), collagen III, MMP3, MMP13, and p62/SQSM1 were observed 24 h after radiation or combined with E. coli challenge. MSCs performed extensive phagocytosis and inactivated bacteria in autolysosomes (Gorbunov et al. 2013). When MSCs were challenged with Gram-positive S. epidermidis (5×107 bacteria/ml) for 3 h, the cells displayed remarkable resistance to the bacterial challenge and sustained confluence over the period of observation. Similar observations to that with E. coli challenge were found as well (Gorbunov et al. 2015). These results suggest that MSCs can contribute to the innate defense response to radiation injury.

MSCs and mitochondrial remodeling

Radiation results in bacterial infection (Kiang et al. 2010). Radiation or bacterial challenge of MSCs results in alteration of the mitochondrial network. Transmission electron microscopy and immunofluorescence microscopy showed that the normal mitochondrial network is a combination of round and elongated organelles containing discrete cristae at high densities. Mitochondrial fusion and fission take place when necessary.

Using electron transmission microscopy, the bacterial challenge resulted in extensive mitochondrial swelling and cristae fragmentation 5 h post-challenge. The entire mitochondrial body almost became reticular by 24 h post-challenge. This structure re-arrangement and fragmentation were triggered by increased expression of immunity-related GTPase family M (IRGM) and inducible nitric oxide synthase (iNOS). Bacterial challenge induced dynamin-related protein 1 (Drp1, a marker of mitochondrial fission) translocation from cytosol to mitochondria, leading to activation of PTEN induced putative kinase 1- parkin RBR E3 ubiquitin protein ligase (PINK1-PARK2) to initiate mitophagy to degrade fragmented mitochondria (Gorbunov et al. 2015). Using Western blotting, proteins of mitofusin-1 (Mfn1, a marker of mitochondrial fusion), PINK1, and PARK2 in MSCs were significantly elevated 24 h after the bacterial challenge. The HSP70 basal level was not affected and no caspase-3 was detected in these cells (Gorbunov et al. 2015). These results suggest that mitophagy but not caspase-dependent apoptosis in MSCs occurs after the bacterial challenge. It is warranted that caspase-independent apoptosis caused by molecular pathways involving with apoptosis-inducible factor (AIF) or by senescence signals of protein 16 (p16) and beta-galactosidase (beta-gal) in MSCs after bacterial challenge shall be explored. MSCs exposed to ionizing irradiation alone also show mitochondrial fission and subsequent fusion as well as mitophagy (Gorbunov et al. 2015).

MSCs and signal transduction

Radiation activates protein kinase B (AKT), c-Jun N-terminal kinases (JNK), and p38 mitogen-activated protein kinases (p38 MAPK) (Kunwar et al. 2012). Felka et al. (2014) reported that NO activated proto-oncogene serine/threonine-protein kinase [c-Raf, part of the extracellular-signal-regulated kinases (ERK) pathway], JNK, p38 MAPK, p53, and a nuclear factor E2-related factor (NRF2)-associated stress response, which may have detrimental consequences for bone remodeling or bone regeneration. Therefore, one can postulate that priming MSCs to elevate pro-survival signaling molecules may enhance MSCs’ multi-functionality as a therapy. MSCs exposed to ionizing radiation results in decreases in AKT and ERK activation and increases in JNK activation (Kiang, Ho, and Smith, unpublished data).

PERSPECTIVE

MSCs have been extensively characterized. They also have been demonstrated to mitigate acute hematopoietic syndrome, gastrointestinal syndrome, and cutaneous syndrome caused by exposure to high doses of ionizing irradiation. Therefore, MSCs as an effective therapy for radiation patients/victims are promising. MSCs can be easily harvested from bone marrow and fat tissues. They can be cultured, grown, and expanded in the laboratory for mass production. Therefore, meeting commercial needs for health maintenance or tissue repair and regeneration can be envisioned and accomplished.

Acknowledgments

The author thanks AFRRI management and leadership and the USUHS External Affairs Office for clearing this manuscript for publication. The views, opinions, and findings contained in this report are those of the author and do not reflect official policy or positions of the Armed Forces Radiobiology Research Institute, the Uniformed Services University of the Health Sciences, the Department of Defense, The National Institutes of Health, or the United Stated government. The commercial products identified in this document do not imply recommendation or endorsement by the Federal Government and do not imply that the products identified are necessarily the best available for the purpose. Research was supported by NIAID YI-AI-5045-04, NIAID AI080553, AFRRI RAB33336, and AFRRI RAB33529 (to JGK).

REFERENCES

  1. Abayomi OK. Pathogenesis of irradiation-induced cognitive dysfunction. Acta Oncol. 1996;35:659–663. doi: 10.3109/02841869609083995. [DOI] [PubMed] [Google Scholar]
  2. Abdel-Mageed AS, Senagore AJ, Pietryga DW, Connors RH, Giambernardi TA, Hay RV, Deng W. Intravenous administration of mesenchymal stem cells genetically modified with extracellular superoxide dismutase improves survival in irradiated mice. Blood. 2009;113:1201–1203. doi: 10.1182/blood-2008-07-170936. [DOI] [PubMed] [Google Scholar]
  3. Acharya MM, Rosi S, Jopson T, Limoli CL. Human neural stem cell transplantation provides long-term restoration of neuronal plasticity in the irradiated hippocampus. Cell Transplant. 2015;24:691–702. doi: 10.3727/096368914X684600. Doi: [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Balduino A, Hurtado SP, Frazão P, Takiya CM, Alves LM, Nasciutti LE, El-Cheikh MC, Borojevic R. Bone marrow subendosteal microenvironment harbours functionally distinct haemosupportive stromal cell populations. Cell Tissue Res. 2005;319:255–266. doi: 10.1007/s00441-004-1006-3. [DOI] [PubMed] [Google Scholar]
  5. Bienz M. The subcellular destinations of APC proteins. Nat Rev Mol Cell Biol. 2002;3:328–338. doi: 10.1038/nrm806. [DOI] [PubMed] [Google Scholar]
  6. Boyer LA1, Plath K, Zeitlinger J, Brambrink T, Medeiros LA, Lee TI, Levine SS, Wernig M, Tajonar A, Ray MK, Bell GW, Otte AP, Vidal M, Gifford DK, Young RA, Jaenisch R. Polycomb complexes repress developmental regulators in murine embryonic stem cells. Nature. 2006;441:349–353. doi: 10.1038/nature04733. [DOI] [PubMed] [Google Scholar]
  7. Butler JM, Rapp SR, Shaw EG. Managing the cognitive effects of brain tumor radiation therapy. Curr Treat Options Oncol. 2006;7:517–523. doi: 10.1007/s11864-006-0026-5. [DOI] [PubMed] [Google Scholar]
  8. Chamberlain G, Fox J, Ashton B, Middleton J. Concise review: mesenchymal stem cells: their phenotype, differentiation capacity, immunological features, and potential for homing. Stem Cells. 2007;25:2739–2749. doi: 10.1634/stemcells.2007-0197. [DOI] [PubMed] [Google Scholar]
  9. Chen D, Zhao M, Mundy GR. Bone morphogenetic proteins. Growth Factors. 2004;22:233–241. doi: 10.1080/08977190412331279890. [DOI] [PubMed] [Google Scholar]
  10. De Luca A, Verardi R, Neva A, Benzoni P, Crescini E, Xia E, Almici C, Calza S, Dell’Era P. Comparative Analysis of Mesenchymal Stromal Cells Biological Properties. ISRN Stem Cells. 2013;2013:674671. [Google Scholar]
  11. Dezawa M, Ishikawa H, Itokazu Y, Yoshihara T, Hoshino M, Takeda S, Ide C, Nabeshima Y. Bone marrow stromal cells generate muscle cells and repair muscle degeneration. Science. 2005;309:314–317. doi: 10.1126/science.1110364. [DOI] [PubMed] [Google Scholar]
  12. Djouad F, Bouffi C, Ghannam S, Noël D, Jorgensen C. Mesenchymal stem cells: innovative therapeutic tools for rheumatic diseases. Nat Rev Rheumatol. 2009;5:392–399. doi: 10.1038/nrrheum.2009.104. [DOI] [PubMed] [Google Scholar]
  13. Felka T, Ulrich C, Rolauffs B, Mittag F, Kluba T, DeZwart P, Ochs G, Bonin M, Nieselt K, Hart ML, Aicher WK. Nitric Oxide activates signaling by c-Raf, MEK, p-JNK, p38 MAPK and p53 in human mesenchymal stromal cells and inhibits their osteogenic differentiation by blocking expression of Runx2. J Stem Cell Res Ther. 2014;4:195. [Google Scholar]
  14. Francois S, Mouiseddine M, Allenet-Lepage B, Voswinkel J, Douay L, Benderitter M, Chapel A. Human mesenchymal stem cells provide protection against radiation-induced liver injury by antioxidative process, vasculature protection, hepatocyte differentiation, and trophic effects. Biomed Res Int. 2013;2013:151679. doi: 10.1155/2013/151679. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Friedenstein AJ, Chailakhjan RK, Lalykina KS. The development of fibroblast colonies in monolayer cultures of guinea-pig bone marrow and spleen cells. Cell Tissue Kinet. 1970;3:393–403. doi: 10.1111/j.1365-2184.1970.tb00347.x. [DOI] [PubMed] [Google Scholar]
  16. Fukumoto R, Cary LH, Gorbunov NV, Lombardini ED, Elliott TB, Kiang JG. Ciprofloxacin modulates cytokine/chemokine profile in serum, improves bone marrow repopulation, and limits apoptosis and autophagy in ileum after whole body ionizing irradiation combined with skin-wound trauma. PLoS One. 2013;8:e58389. doi: 10.1371/journal.pone.0058389. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Garg S, Wang W, Prabath BG, Boerma M, Wang J, Zhou D, Hauer-Jensen M. Bone marrow transplantation helps restore the intestinal mucosal barrier after total body irradiation in mice. Radiat Res. 2014;181:229–239. doi: 10.1667/RR13548.1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Gorbunov NV, Elliott TB, McDaniel DP, Lund K, Liao PJ, Zhai M, Kiang JG. Up-regulation of autophagy defense mechanisms in mouse mesenchymal stromal cells in response to ionizing irradiation followed by bacterial challenge. INTECH. 2013;2013:331–350. [Google Scholar]
  19. Gorbunov NV, McDaniel DP, Zhai M, Liao PJ, Garrison BR, Kiang JG. Autophagy and mitochondrial remodelling in mouse mesenchymal stromal cells challenged with Staphylococcus epidermidis. J Cell Mol Med. 2015;19:1133–1150. doi: 10.1111/jcmm.12518. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Greenberger JS, Epperly M. Bone marrow-derived stem cells and radiation response. Semin Radiat Oncol. 2009;19:133–139. doi: 10.1016/j.semradonc.2008.11.006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Gronthos S, Zannettino AC, Hay SJ, Shi S, Graves SE, Kortesidis A, Simmons PJ. Molecular and cellular characterisation of highly purified stromal stem cells derived from human bone marrow. J Cell Sci. 2003;116(Pt 9):1827–1835. doi: 10.1242/jcs.00369. [DOI] [PubMed] [Google Scholar]
  22. Hao L, Wang J, Zou Z, Yan G, Dong S, Deng J, Ran X, Feng Y, Luo C, Wang Y, Cheng T. Transplantation of BMSCs expressing hPDGF-A/hBD2 promotes wound healing in rats with combined radiation-wound injury. Gene Ther. 2009;16:34–42. doi: 10.1038/gt.2008.133. [DOI] [PubMed] [Google Scholar]
  23. Hartmann C1. A Wnt canon orchestrating osteoblastogenesis. Trends Cell Biol. 2006;16:151–158. doi: 10.1016/j.tcb.2006.01.001. [DOI] [PubMed] [Google Scholar]
  24. Hu KX, Sun QY, Guo M, Ai HS. The radiation protection and therapy effects of mesenchymal stem cells in mice with acute radiation injury. Br J Radiol. 2010;83:52–58. doi: 10.1259/bjr/61042310. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Izadpanah R, Trygg C, Patel B, Kriedt C, Dufour J, Gimble JM, Bunnell BA. Biologic properties of mesenchymal stem cells derived from bone marrow and adipose tissue. J Cell Biochem. 2006;99:1285–1297. doi: 10.1002/jcb.20904. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Jiang Y, Vaessen B, Lenvik T, Blackstad M, Reyes M, Verfaillie CM. Multipotent progenitor cells can be isolated from postnatal murine bone marrow, muscle, and brain. Exp Hematol. 2002;30:896–904. doi: 10.1016/s0301-472x(02)00869-x. [DOI] [PubMed] [Google Scholar]
  27. Kiang JG, Garrison BR, Burns TM, Zhai M, Dews IC, Ney PH, Cary LH, Fukumoto R, Elliott TB, Ledney GD. Wound trauma alters ionizing radiation dose assessment. Cell Biosci. 2012;2:20. doi: 10.1186/2045-3701-2-20. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Kiang JG, Gorbunov NV. Bone marrow mesenchymal stem cells increase survival after ionizing irradiation combined with wound trauma: characterization and therapy. J Cell Sci Ther. 2014;5:6. doi: 10.4172/2157-7013.1000190. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Kiang JG, Jiao W, Cary LH, Mog SR, Elliott TB, Pellmar TC, Ledney GD. Wound trauma increases radiation-induced mortality by activation of iNOS pathway and elevation of cytokine concentrations and bacterial infection. Radiat Res. 2010;173:319–332. doi: 10.1667/RR1892.1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Kiang JG, Smith JT, Anderson MN, Swift JM, Christensen CL, Gupta P, Balakathiresan N, Maheshwari RK. Hemorrhage Exacerbates Radiation Effects on Survival, Leukocytopenia, Thrombopenia, Erythropenia, Bone Marrow Cell Depletion and Hematopoiesis, and Inflammation-Associated microRNAs Expression in Kidney. PLoS One. 2015;10(9):e0139271. doi: 10.1371/journal.pone.0139271. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Kléber M, Sommer L. Wnt signaling and the regulation of stem cell function. Curr Opin Cell Biol. 2004;16:681–687. doi: 10.1016/j.ceb.2004.08.006. [DOI] [PubMed] [Google Scholar]
  32. Kolf CM, Cho E, Tuan RS. Mesenchymal stromal cells. Biology of adult mesenchymal stem cells: regulation of niche, self-renewal and differentiation. Arthritis Res Ther. 2007;9:204. doi: 10.1186/ar2116. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Krebsbach PH, Kuznetsov SA, Bianco P, et al. Bone marrow stromal cells: characterization and clinical application. Crit Rev Oral Biol Med. 1999;10:165–181. doi: 10.1177/10454411990100020401. [DOI] [PubMed] [Google Scholar]
  34. Kunwar A, Adhikary B, Jayakumar S, Barik A, Chattopadhyay S, Raghukumar S, Priyadarsini KI. Melanin, a promising radioprotector: mechanisms of actions in a mice model. Toxicol Appl Pharmacol. 2012;264:202–211. doi: 10.1016/j.taap.2012.08.002. [DOI] [PubMed] [Google Scholar]
  35. Le Blanc K, Frassoni F, Ball L, Locatelli F, Roelofs H, Lewis I, Lanino E, Sundberg B, Bernardo ME, Remberger M, Dini G, Egeler RM, Bacigalupo A, Fibbe W, Ringdén O. Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study. Lancet. 2008;371:1579–1586. doi: 10.1016/S0140-6736(08)60690-X. [DOI] [PubMed] [Google Scholar]
  36. Ledney GD, Elliott TB. Combined injury: factors with potential to impact radiation dose assessments. Health Phys. 2010;98:145–152. doi: 10.1097/01.HP.0000348466.09978.77. [DOI] [PubMed] [Google Scholar]
  37. Metcalf D. The unsolved enigmas of leukemia inhibitory factor. Stem Cells. 2003;21:5–14. doi: 10.1634/stemcells.21-1-5. [DOI] [PubMed] [Google Scholar]
  38. Meyers CA, Brown PD. Role and relevance of neurocognitive assessment in clinical trials of patients with CNS tumors. J Clin Oncol. 2006;24:1305–1309. doi: 10.1200/JCO.2005.04.6086. [DOI] [PubMed] [Google Scholar]
  39. Németh K, Leelahavanichkul A, Yuen PS, Mayer B, Parmelee A, Doi K, Robey PG, Leelahavanichkul K, Koller BH, Brown JM, Hu X, Jelinek I, Star RA, Mezey E. Bone marrow stromal cells attenuate sepsis via prostaglandin E(2)-dependent reprogramming of host macrophages to increase their interleukin-10 production. Nat Med. 2009;15:42–49. doi: 10.1038/nm.1905. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Nuttall ME, Gimble JM. Controlling the balance between osteoblastogenesis and adipogenesis and the consequent therapeutic implications. Curr Opin Pharmacol. 2004;4:290–294. doi: 10.1016/j.coph.2004.03.002. [DOI] [PubMed] [Google Scholar]
  41. Owen M, Friedenstein AJ. Stromal stem cells: marrow-derived osteogenic precursors. Ciba Found Symp. 1988;136:42–60. doi: 10.1002/9780470513637.ch4. [DOI] [PubMed] [Google Scholar]
  42. Pittenger MF1, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, Moorman MA, Simonetti DW, Craig S, Marshak DR. Multilineage potential of adult human mesenchymal stem cells. Science. 1999;284:143–147. doi: 10.1126/science.284.5411.143. [DOI] [PubMed] [Google Scholar]
  43. Riccobono D, Agay D, Scherthan H, Forcheron F, Vivier M, Ballester B, Meineke V, Drouet M. Application of adipocyte-derived stem cells in treatment of cutaneous radiation syndrome. Health Phys. 2012;103:120–126. doi: 10.1097/HP.0b013e318240595b. [DOI] [PubMed] [Google Scholar]
  44. Saha S, Bhanja P, Kabarriti R, Liu L, Alfieri AA, Guha C. Bone marrow stromal cell transplantation mitigates radiation-induced gastrointestinal syndrome in mice. PLoS One. 2011;6:e24072. doi: 10.1371/journal.pone.0024072. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Simmons PJ, Torok-Storb B. Identification of stromal cell precursors in human bone marrow by a novel monoclonal antibody, STRO-1. Blood. 1991;78:55–62. [PubMed] [Google Scholar]
  46. Tian Y, Deng YB, Huang YJ, Wang Y. Bone marrow-derived mesenchymal stem cells decrease acute graft-versus-host disease after allogeneic hematopoietic stem cells transplantation. Immunol Invest. 2008;37:29–42. doi: 10.1080/08820130701410223. [DOI] [PubMed] [Google Scholar]
  47. Tsutsumi S, Shimazu A, Miyazaki K, Pan H, Koike C, Yoshida E, Takagishi K, Kato Y. Retention of multilineage differentiation potential of mesenchymal cells during proliferation in response to FGF. Biochem Biophys Res Commun. 2001;288:413–419. doi: 10.1006/bbrc.2001.5777. [DOI] [PubMed] [Google Scholar]
  48. Zaragosi LE, Ailhaud G, Dani C. Autocrine fibroblast growth factor 2 signaling is critical for self-renewal of human multipotent adipose-derived stem cells. Stem Cells. 2006;24:2412–2419. doi: 10.1634/stemcells.2006-0006. [DOI] [PubMed] [Google Scholar]

RESOURCES