We attempted to rescue supralethally irradiated (SLI) mice by transplantation of hematopoietic stem cells (HSCs) plus thymus from variously aged donors (fetus, newborn and adult). Although the transplantations of these kinds of HSCs alone showed a very short survival, newborn liver cells (NLCs) (as the source of HSCs) plus newborn thymus (NT) transplantation markedly improved the survival rate. The transplantation attenuated severe damage in the small intestine, which is one of the major causes of death by SLI. In addition, the donor-derived CD4+ T cells significantly increased with additional NT transplantation. The production of interleukin (IL)-7 and keratinocyte growth factor, which plays a crucial role in protection against radiation injury in the intestine, was the highest in NT. Finally, SLI mice that had received NLC plus IL-7−/− NT transplantation plus IL-7 injection showed improved survival, weight recovery and an elevated number of CD4+ T cells compared with the mice that had received NLC plus IL-7−/− NT or plus IL-7 injection alone. These findings suggest that NLCs plus NT transplantation can rescue SLI mice most effectively, and that high production of IL-7 in NT plays a crucial role with induction of CD4+ T cells.
In recent years, bone marrow transplantation (BMT) has become a powerful strategy for the treatment of intractable diseases, such as hematological disorders (leukemia, lymphoma and aplastic anemia), congenital immunodeficiencies, metabolic disorders, autoimmune diseases and malignant tumors.1 Using various animal models, we have found that allogeneic BMT can be used for the treatment of such diseases.2, 3, 4, 5, 6, 7, 8, 9 The basic theory is to replace pathogenic hematopoietic cells of hosts with normal hematopoietic stem cells (HSCs) of donors following lethal irradiation.
Exposure to supralethal irradiation (SLI) can occur, for example, in criticality accidents or in the treatment of malignant tumors.10, 11, 12, 13 High doses of irradiation induce severe damage not only in hematopoietic cells but also in other organs such as the gastrointestinal tract and brain,14 leading to early death. Conventional BMT is thus ineffective for SLI recipients, because the organ damage is overwhelming. Indeed, HSC transplantation was unable to rescue a recent case of criticality accident, even though donor-derived cells were detected.15, 16 Rescue from SLI is thus extremely difficult.
The thymus is the central organ of T-cell development. We have previously reported that BMT plus thymus transplantation can accelerate hematopoietic recovery and improve survival rate, and can be used to treat autoimmune diseases in recipients such as aged or chimeric resistant hosts,7, 17 in which conventional BMT is difficult.
Interleukin (IL)-7 is produced by thymic epithelial cells, marrow stromal cells, fibroblasts and intestinal epithelia, and plays a crucial role in the early T-cell development and the functions in the thymus.18, 19, 20, 21, 22, 23, 24 In addition, IL-7 engages in mucosal immunity, including the development of γδ T cells.25, 26, 27 Notably, IL-7 signals have also been reported as an important factor in the regeneration of the gastrointestinal cells after irradiation.28 Keratinocyte growth factor (KGF) is the significant cytokine for generating epithelial cells.29 In embryogenesis, both KGF produced by thymocytes and IL-7 by thymic epithelial cells play a part in the development of the thymus.30 Additionally, KGF is effective in treating intestine injured by irradiation and chemotherapy.31
In the present study, we attempted to rescue SLI mice using HSC transplantation plus thymus transplantation from variously aged donors, since the functions of the thymus greatly differ with age.32, 33 We here show that the transplantation of newborn liver cell (NLCs) plus newborn thymus (NT) can most effectively rescue SLI mice. It is likely that the high production of IL-7 by NT transplantation plays an important role in the induction of CD4+ T cells.
Materials and methods
Female 6- to 8-week-old, newborn (⩽48 h after birth) and 16-day fetus C57BL/6 (B6) (H-2b) and BALB/c (H-2d) mice were obtained from Shimizu Laboratory Supplies (Shizuoka, Japan) and maintained until use in our animal facilities under specific pathogen-free conditions. IL-7 gene null (IL-7−/−) mice with B6 background were kindly provided by Professor Ikuta from Kyoto University (Kyoto, Japan).27
HSCs and thymus transplantation
The 6- to 8-week-old female BALB/c mice received lethal irradiation (7 Gy) or SLI (9.5 Gy) 1 day before HSC transplantation. The next day, 1 × 107 B6 HSCs were injected intravenously into these mice. Bone marrow cells were collected from the femurs and tibias of 6- to 8-week-old B6 mice. Newborn and fetal livers were obtained and single-cell suspensions were created for the use of NLCs and fetal liver cells as the source of HSCs.34, 35 Adult thymus (AT), NT and fetal thymus (FT) tissues were removed from the aged mice. For thymus transplantation, one-quarter of the AT, or one NT or one FT was simultaneously transplanted under the renal capsule in some recipients with HSC transplantation. Thymus transplantation alone was also performed in other mice.
IL-7 treatment in vivo
Recombinant mouse IL-7 (Perpro Tech EC, London, UK) in PBS was injected intraperitoneally into chimeric mice for 7 days after HSC transplantation (1 μg per mice per day). Control mice were injected with PBS alone.
Reverse transcription-PCR analysis was employed for the determination of IL-7 mRNA. In brief, total RNA was extracted from each isolated thymus using RNagent (Promega, Madison, WI, USA) according to the manufacturer's instructions. Reverse transcription of 1 μg of RNA to cDNA was performed using oligo(dT) (Perkin Elmer Cetus, Norwork, CT, USA). Primer sequences of IL-7 and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and PCR condition were as follows: IL-7 (forward), 5′-IndexTermACATCATCTGAGTGCCACA-3′; IL-7 (reverse), 5′-IndexTermCTCTCAGTAGTCTCTTTAG-3′ (355 bp); KGF (forward), 5′-IndexTermATCCTGCCAACTCTGCTACAGA-3′; KGF (reverse), 5′-IndexTermCTTCCCTTTGACAGGAATCCCCTT3′; GAPDH (forward), 5′-IndexTermACCACAGTCCATGCCATCAC-3′; GAPDH (reverse), 5′-IndexTermTCCACCACCCTGTTGCTGTA-3′ (452 bp). Each reaction was performed at 94 °C for 30 s for denaturation, then optimal annealing temperature (IL-7, 45 °C; KGF, 55 °C; GAPDH, 55 °C) for 30 s and 72 °C for 30 s for elongation (35 cycles). PCR products were analyzed by electrophoresis in 2% agarose gels and made visible by staining with ethidium bromide.
Each thymus tissue sample (1 mg per sample) was lysed on ice for 40 min in 20 μl of cell lysis buffer (0.5% Nonidet P-40 (Sigma, St Louis, MO, USA), 0.15 M NaCl, 5 mM EDTA, 50 mM Tris–HCl, pH 7.2) supplemented with a protease inhibitor cocktail (Roche Molecular Biochemicals, Indianapolis, IN, USA). Following centrifugation at 8000 r.p.m. for 10 min, the lysate supernatants were normalized for protein concentration using the Bradford reagents (Pierce Chemical, Rockford, IL, USA). Samples were boiled for 5 min in SDS-reducing buffer, separately treated by SDS–PAGE (12% acryl-amide, wt/vol), and then electrophoretically transferred onto nitrocellulose membranes. Membranes were probed for invariant chain with the IN-1 Moabs. Anti-human KGF antibody (goat anti-mouse affinity-purified IgG) (R&D Systems, Minneapolis, MN, USA) and anti-mouse IL-7 antibody (goat anti-mouse affinity-purified IgG) were applied at 1:100 dilution. Binding was detected using a horseradish peroxidase-conjugated anti-goat IgG (American Pharmacia Biotech, Piscataway, NJ, USA) diluted at 1:1500 and visualized by chemiluminescence.
Analysis of surface markers and the numbers of lymphocytes by flow cytometry
Surface markers on lymphocytes from peripheral blood and spleen cells were analyzed by three-color fluorescence staining using a FACScan system (Becton Dickinson, Franklin Lakes, NJ, USA). FITC-conjugated anti-H-2Kb MoAbs (Pharmingen, San Diego, CA, USA) were used to determine chimerism. FITC-, phycoerythrin- or biotin-conjugated CD4, CD8 or B220 (Becton Dickinson or Pharmingen) was used for analyses of lymphocyte subsets. Avidin-Cy5 (Dako, Kyoto, Japan) was used for the third color in the avidin/biotin system. The numbers of lymphocyte subsets in peripheral blood or in spleen cells were calculated as the total lymphocyte numbers of WBCs measured by SF-3000 with SFVU-1 unit (Sysmex, Kobe, Japan), or as the total lymphocyte numbers of spleen cells multiplied by the percentage of the lymphocyte cells.
The small intestine, grafted thymus under the renal capsule and other organs from chimeric mice were fixed in 10% formaldehyde solution and embedded in paraffin. Sections 4-μm thick were prepared and stained using hematoxylin and eosin. Histology was examined under microscopy.
Nonparametric analyses (paired or unpaired Mann–Whitney U- and log-rank tests) were performed using StatView software (Abacus Concepts, Berkeley, CA, USA). Values of P<0.05 were considered statistically significant.
Survival rates and chimerism in SLI mice receiving HSCs with or without thymus transplantation from variously aged donors
We first examined the effects on survival rates in SLI (9.5 Gy) mice that had received HSCs with or without thymus transplantation from variously aged (fetus, newborn and adult) donors (Figure 1). In total, 80% of BALB/c mice that had been irradiated with a conventional low dose (7 Gy) survived >100 days after the transplantation of 1 × 107 bone marrow cells of B6 mice. In contrast, most of the 9.5-Gy-irradiated BALB/c mice died within 14 days after the transplantation of 1 × 107 HSCs from variously aged B6 mice (Figure 1a), since BALB/c mice are radio-sensitive and 9.5 Gy is an SLI dose. Next, we performed additional thymus transplantation in SLI mice (Figure 1b). Interestingly, NLCs with NT transplantation significantly improved the survival rate (70% survival at 100 days after transplantation), in comparison with NLC transplantation alone and all the other combinations. NT transplantation alone did not improve the survival rate. The engrafted thymus showed a normal structure under the renal capsule, and normal T-cell differentiation was observed in the thymus 8 weeks after transplantation (Figure 2).
Histology and body weight in SLI mice receiving NLC plus NT transplantation
Next, we investigated the causes of death in SLI mice. Histologically, the most damaged organ was the small intestine in the mice that had received NLC transplantation alone. In contrast to normal small intestine (Figure 3a; i), the mucosa displayed marked necrosis, and only a few cryptae were left 7 days after transplantation (Figure 3a; ii). However, with NT transplantation, severity was attenuated (Figure 3a; iii) and the mucosa with cryptae displayed good regeneration 14 days after the transplantation (Figure 3a; iv). The body weight of SLI mice that had received NLC transplantation alone was significantly reduced compared with conventional dose (7 Gy)-irradiated mice at 7 days (Figure 3b). However, it was significantly recovered with additional NT transplantation. SLI mice that had received HSCs alone or HSCs with AT or FT transplantation showed short survival rates (data not shown).
Analyses of chimerism and lymphocyte subsets from SLI mice receiving NLCs with or without NT transplantation
Supralethal irradiation mice that had received NLCs plus NT transplantation showed full donor-type chimerism (H-2Kb+) at 2 weeks after transplantation, and it continued for more than 12 weeks (Figure 4a). However, the mice that had received NLC transplantation alone also showed the same level of donor chimerism at 1 week but showed short survival. We then examined the percentage and the number of the donor-derived lymphocyte subsets in the mice at that time. Interestingly, both the percentage and the number of CD4+ T cells significantly increased in the mice that had received NLCs plus NT transplantation, compared with those receiving NLC transplantation alone, in both peripheral blood and spleen (Figure 4b). In addition, the number of B cells significantly increased in peripheral blood.
Analyses of IL-7 and KGF production in thymus grafts
We next examined IL-7 and KGF production in freshly isolated thymus grafts from the donors as one of the mechanisms, since IL-7 and KGF play an important role in recovery from radiation-induced intestinal injury.28, 31 Interestingly, both mRNA and protein levels of IL-7 and KGF were the highest in NT, second highest in FT and the lowest in AT (Figure 5).
Effects of IL-7 in NT on rescue of SLI mice receiving NLCs plus NT transplantation
We finally examined the role of IL-7 produced by NT in the rescue of SLI mice, because mesenchymal cells contained in NLCs also produce IL-7. Using IL-7 null mice,27 we carried out NLC transplantation from wild-type (IL-7+/+) mice with or without IL-7−/− NT transplantation in SLI mice with or without IL-7 injections in vivo. The SLI mice that had received NLCs alone reached 50% mortality on the seventh day after transplantation (Figure 1a). We therefore continued the injection of IL-7 for 7 days (1 μg per day/mouse). Although the mice that had received NLC transplantation alone (non-treatment) soon died, as shown in Figure 1, either of the additional IL-7−/− NT transplantation or IL-7 treatments slightly improved the survival rate (Figure 6a). In contrast, the NLC+IL-7−/− NT transplantation plus IL-7 treatment showed a further prolonged survival. Histologically, whereas mucosa was necrotic and many cryptae were absent in SLI mice with transplantation of NLC alone (Figure 6b; ii), the pathologic findings were attenuated by addition of IL-7−/− NT transplantation with IL-7 treatment (Figure 6b; i). In the recovery of weight loss and the induction of both the percentage and the number of CD4+ T cells in the spleen, NLCs plus IL-7−/− NT transplantation plus IL-7 treatment also showed the most effects, and NLCs plus IL-7−/− NT transplantation or plus IL-7 treatment showed a slight effect compared with NLC transplantation alone (non-treatment) (Figures 6c).
In the present study, we investigated how to rescue SLI mice using HSCs plus thymus transplantation. Although HSC transplantation alone was ineffective, additional thymus transplantation, particularly NT thymus transplantation, significantly improved survival rates. The transplantation attenuated severe intestinal damage with weight recovery and increased the number of CD4+ T cells in the SLI-recipient mice. The production of IL-7 was elevated in NT, and NLCs plus IL-7−/− NT transplantation showed little effect in the rescue of SLI mice. These results suggest that NLCs plus NT transplantation can rescue SLI mice most effectively, and that high production of IL-7 in NT plays a crucial role as one of the mechanisms with induction of CD4+ T cells.
First, we examined the survival effects of HSCs and thymus transplantation from variously aged donors. Although all kinds of HSC transplantation alone showed a very short survival, NLCs plus NT transplantation markedly improved the survival rate (Figure 1). In the analyses of the causes of death the SLI mice that had received NLC transplantation alone showed severe intestinal injury with significant weight loss (Figure 3). These findings are comparable with acute irradiation-induced gastrointestinal syndrome, which occurs after exposure to high-dose radiation.14 However, additional NT transplantation attenuated intestinal damage, and the weight was recovered. These findings suggest that NLCs with NT transplantation can rescue the SLI mice with a potential protection against intestinal injury following irradiation.
We next examined chimerism and lymphocyte subsets in the mice that had received NLCs with or without NT transplantation. The donor-derived chimerism itself did not differ in the presence or absence of NT transplantation at an early phase after transplantation (Figure 4a), suggesting that SLI mice cannot be rescued by hematopoietic reconstitution alone. However, the CD4+ T cells were significantly higher in the mice that had received NLCs with NT transplantation than in the mice that had received NLC transplantation alone (Figure 4b); and the number of B cells also significantly increased in peripheral blood. Some of the elevated CD4+ T cells are very likely to be developed from the engrafted thymus, and the B cells are likely to be increased by the IL-7 as an inducible cytokine for early B cells from the thymus. Thus, the increased cells, especially the CD4+ T cells, should play a critical role in the rescue, although it is unknown why the number of CD8+ T cells was unchanged.
We then analyzed the functions of each thymus graft. Interestingly, the production of IL-7 and KGF, which regenerate the intestinal epithelium after irradiation,28, 31 was highest in NT (Figure 5). Therefore, we finally examined the role of elevated IL-7 production by the NT transplantation in the rescue of SLI mice. We found that both IL-7−/− NT transplantation plus treatments of IL-7 injection are essential for survival, the recovery of weight and the induction of CD4+ T cells, whereas either IL-7−/− NT transplantation or IL-7 injection alone showed only a slight effect (Figure 6). Although we performed IL-7 treatment for only 7 days in the SLI mice that had received NLCs and IL-7−/− NT, mesenchymal cells such as BM stromal cells or fibroblasts from the NLCs and/or recovered thymic epithelial cells in host thymus began to produce IL-7 later, leading to long survival. These findings suggest that although elevated IL-7 plays a significant role, the thymus graft itself is also needed for the satisfactory rescue of SLI mice.
The elevation of IL-7 and the subsequent induction of CD4+ T cells by NT transplantation thus seem to be responsible for the rescue of SLI mice. Although we could not find detectable levels of IL-7 in serum by ELISA (data not shown) and no significant difference in IL-7R expression by immunohistochemistry in the intestine of the SLI mice that received NLCs in the presence or absence of NT (data not shown),36 the signal should be one of the effective factors for the rescue of the SLI mice, given the results. Alternatively, although we did not examine the role of KGF, it may be also effective to treat the injury in the small intestine directly.31 In this respect, the IL-7 signal itself also induces intraepithelial lymphocytes to produce KGF.37 Concerning the induced CD4+ T cells, they may be protective against infection or effective in repairing the injured intestine.38, 39 In this respect, T cells from the NT were shown to be highly proliferative and functional for the production of various cytokines compared with AT.32, 33 This might also facilitate the rescue of SLI mice.
Although we did not examine the mechanism of the rescue directly, given the above results, the high growth activity of NT is likely to be critical in the elevation of IL-7 and KGF. In fact, although the size of the AT graft did not change or slightly decreased after reconstitution,17 grafted NT or FT grew rapidly under the renal capsule with high proliferative acivity,32, 33 and the size became close to the grafted AT by 8 weeks after transplantation, even though their initial volume and weight was about 1/10 less than the AT (data not shown). The activity may also help regenerate or completely repair damaged organs in SLI mice. Although FT has a potential close to NT with the second highest level of IL-7 and KGF production, the levels may be insufficient for the rescue of the mice. In addition, the accompanying hormonal and cellular factors apart from IL-7, KGF and CD4+ T cells might also be involved practically. Further analyses are needed for a detailed explanation of these mechanisms.
Finally, the present method might also be effective in critically accident patients or those with advanced or metastatic malignant tumors, for whom excess irradiation or chemotherapy is necessary as treatment. We have also recently found that, even if the thymus donor is different from the HSC donor, the effect is comparable to that seen with transplantation from the same donor (submitted for publication). In addition, different aged combinations of HSCs and NT, such as bone marrow cells plus NT or fetal liver cells plus NT transplantation were also effective for rescue of the SLI recipient (data not shown). Although there are ethical issues involved, an NT graft could be obtained from patients with congenital heart diseases or from aborted fetuses, as previously utilized for the graft.40
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We thank Ms Y Tokuyama, Ms R Hayashi and Ms A Kitajima for technical assistance and Ms K Ando for secretarial assistance. This work was supported by Research Grant C from Kansai Medical University.
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Ryu, T., Hosaka, N., Miyake, T. et al. Transplantation of newborn thymus plus hematopoietic stem cells can rescue supralethally irradiated mice. Bone Marrow Transplant 41, 659–666 (2008). https://doi.org/10.1038/sj.bmt.1705957
- newborn thymus
- hematopoietic stem cells
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