The relative ineffectiveness of hematopoietic stem cells in reaching the bone marrow upon transplantation combined with the limited number of these cells available is a major reason for graft failure and delayed hematopoietic recovery. Hence, the development of strategies that could enhance homing is of high interest. Here, we provide evidence that homing is severely impaired postexposure to ionizing radiation (IR) in mice, an effect we found was time dependent and could be partially rescued using mesenchymal stromal cell (MSC) therapy. In an attempt to further increase homing, we took advantage of our observation that the granulocyte colony stimulating factor (G-CSF), a cytokine known to induce cell mobilization, is increased in the marrow of mice shortly after their exposure to IR. As such, we developed a truncated, yet functional, soluble G-CSF receptor (solG-CSFR), which we hypothesized could act as a decoy and foster homing. Using MSCs or conditioned media as delivery vehicles, we show that an engineered solG-CSFR has the potential to increase homing and hematopoietic reconstitution in mice. Altogether, our results provide novel findings at the interplay of IR and stromal cell therapy and present the regulation of endogenous G-CSF as an innovative proof-of-concept strategy to manipulate hematopoietic cell homing.
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References
1.
RochaV, BroxmeyerHE. 2010. New approaches for improving engraftment after cord blood transplantation. Biol Blood Marrow Transplant, 16:S126–S132.
2.
JetmoreA, PlettPA, TongX, WolberFM, BreeseR, AbonourR, Orschell-TraycoffCM, SrourEF. 2002. Homing efficiency, cell cycle kinetics, and survival of quiescent and cycling human CD34(+) cells transplanted into conditioned NOD/SCID recipients. Blood, 99:1585–1593.
3.
PetitI, Szyper-KravitzM, NaglerA, LahavM, PeledA, HablerL, PonomaryovT, TaichmanRS, Arenzana-SeisdedosFet al. 2002. G-CSF induces stem cell mobilization by decreasing bone marrow SDF-1 and up-regulating CXCR4. Nat Immunol, 3:687–694.
4.
SatoN, SawadaK, TakahashiTA, MogiY, AsanoS, KoikeT, SekiguchiS. 1994. A time course study for optimal harvest of peripheral blood progenitor cells by granulocyte colony-stimulating factor in healthy volunteers. Exp Hematol, 22:973–978.
5.
AiutiA, WebbIJ, BleulC, SpringerT, Gutierrez-RamosJC. 1997. The chemokine SDF-1 is a chemoattractant for human CD34+ hematopoietic progenitor cells and provides a new mechanism to explain the mobilization of CD34+ progenitors to peripheral blood. J Exp Med, 185:111–120.
6.
PonomaryovT, PeledA, PetitI, TaichmanRS, HablerL, SandbankJ, Arenzana-SeisdedosF, MagerusA, CaruzAet al.2000. Induction of the chemokine stromal-derived factor-1 following DNA damage improves human stem cell function. J Clin Invest, 106:1331–1339.
7.
BoitanoAE, WangJ, RomeoR, BouchezLC, ParkerAE, SuttonSE, WalkerJR, FlavenyCA, PerdewGHet al.2010. Aryl hydrocarbon receptor antagonists promote the expansion of human hematopoietic stem cells. Science, 329:1345–1348.
8.
CampbellTB, HangocG, LiuY, PollokK, BroxmeyerHE. 2007. Inhibition of CD26 in human cord blood CD34+ cells enhances their engraftment of nonobese diabetic/severe combined immunodeficiency mice. Stem Cells Dev, 16:347–354.
9.
ChristophersonKW2nd, HangocG, MantelCR, BroxmeyerHE. 2004. Modulation of hematopoietic stem cell homing and engraftment by CD26. Science, 305:1000–1003.
CastelloS, PodestaM, MendittoVG, IbaticiA, PittoA, FigariO, ScarpatiD, MagrassiL, BacigalupoA, PiaggioG, FrassoniF. 2004. Intra-bone marrow injection of bone marrow and cord blood cells: an alternative way of transplantation associated with a higher seeding efficiency. Exp Hematol, 32:782–787.
12.
FrassoniF, GualandiF, PodestaM, RaiolaAM, IbaticiA, PiaggioG, SessaregoM, SessaregoN, GobbiMet al.2008. Direct intrabone transplant of unrelated cord-blood cells in acute leukaemia: a phase I/II study. Lancet Oncol, 9:831–839.
13.
BrunsteinCG, BarkerJN, WeisdorfDJ, DeforTE, McKennaD, ChongSY, MillerJS, McGlavePB, WagnerJE. 2009. Intra-BM injection to enhance engraftment after myeloablative umbilical cord blood transplantation with two partially HLA-matched units. Bone Marrow Transplant, 43:935–940.
14.
BallLM, BernardoME, RoelofsH, LankesterA, CometaA, EgelerRM, LocatelliF, FibbeWE. 2007. Cotransplantation of ex vivo expanded mesenchymal stem cells accelerates lymphocyte recovery and may reduce the risk of graft failure in haploidentical hematopoietic stem-cell transplantation. Blood, 110:2764–2767.
15.
BernardoME, BallLM, CometaAM, RoelofsH, ZeccaM, AvanziniMA, BertainaA, VintiL, LankesterAet al.2011. Co-infusion of ex vivo-expanded, parental MSCs prevents life-threatening acute GVHD, but does not reduce the risk of graft failure in pediatric patients undergoing allogeneic umbilical cord blood transplantation. Bone Marrow Transplant, 46:200–207.
16.
KocON, GersonSL, CooperBW, DyhouseSM, HaynesworthSE, CaplanAI, LazarusHM. 2000. Rapid hematopoietic recovery after coinfusion of autologous-blood stem cells and culture-expanded marrow mesenchymal stem cells in advanced breast cancer patients receiving high-dose chemotherapy. J Clin Oncol, 18:307–316.
17.
BernardoME, CometaAM, LocatelliF. 2011. Mesenchymal stromal cells: a novel and effective strategy for facilitating engraftment and accelerating hematopoietic recovery after transplantation?Bone Marrow Transplant, 47:323–329.
18.
ChanSL, ChoiM, WnendtS, KrausM, TengE, LeongHF, MerchavS. 2007. Enhanced in vivo homing of uncultured and selectively amplified cord blood CD34+ cells by cotransplantation with cord blood-derived unrestricted somatic stem cells. Stem Cells, 25:529–536.
19.
NakaoN, NakayamaT, YahataT, MugurumaY, SaitoS, MiyataY, YamamotoK, NaoeT. 2010. Adipose tissue-derived mesenchymal stem cells facilitate hematopoiesis in vitro and in vivo: advantages over bone marrow-derived mesenchymal stem cells. Am J Pathol, 177:547–554.
20.
NoortWA, KruisselbrinkAB, in't AnkerPS, KrugerM, van BezooijenRL, de PausRA, HeemskerkMH, LowikCW, FalkenburgJH, WillemzeR, FibbeWE. 2002. Mesenchymal stem cells promote engraftment of human umbilical cord blood-derived CD34(+) cells in NOD/SCID mice. Exp Hematol, 30:870–878.
21.
MaijenburgMW, van der SchootCE, VoermansC. 2012. Mesenchymal stromal cell migration: possibilities to improve cellular therapy. Stem Cells Dev, 21:19–29.
22.
NaldiniL, BlomerU, GallayP, OryD, MulliganR, GageFH, VermaIM, TronoD. 1996. In vivo gene delivery and stable transduction of nondividing cells by a lentiviral vector. Science, 272:263–267.
23.
CarbonneauCL, DesparsG, Rojas-SutterlinS, FortinA, LeO, HoangT, BeausejourCM. 2012. Ionizing radiation-induced expression of INK4a/ARF in murine bone marrow-derived stromal cell populations interferes with bone marrow homeostasis. Blood, 119:717–726.
24.
CollisSJ, NeutzelS, ThompsonTL, SwartzMJ, DillehayLE, CollectorMI, SharkisSJ, DeWeeseTL. 2004. Hematopoietic progenitor stem cell homing in mice lethally irradiated with ionizing radiation at differing dose rates. Radiat Res, 162:48–55.
25.
MorikawaS, MabuchiY, KubotaY, NagaiY, NiibeK, HiratsuE, SuzukiS, Miyauchi-HaraC, NagoshiNet al.2009. Prospective identification, isolation, and systemic transplantation of multipotent mesenchymal stem cells in murine bone marrow. J Exp Med, 206:2483–2496.
26.
RomboutsWJ, PloemacherRE. 2003. Primary murine MSC show highly efficient homing to the bone marrow but lose homing ability following culture. Leukemia, 17:160–170.
27.
WangL, LiuY, KalajzicZ, JiangX, RoweDW. 2005. Heterogeneity of engrafted bone-lining cells after systemic and local transplantation. Blood, 106:3650–3657.
28.
TabatabaiG, FrankB, MohleR, WellerM, WickW. 2006. Irradiation and hypoxia promote homing of haematopoietic progenitor cells towards gliomas by TGF-beta-dependent HIF-1alpha-mediated induction of CXCL12. Brain, 129:2426–2435.
KoppHG, AvecillaST, HooperAT, RafiiS. 2005. The bone marrow vascular niche: home of HSC differentiation and mobilization. Physiology, 20:349–356.
31.
KomarovPG, KomarovaEA, KondratovRV, Christov-TselkovK, CoonJS, ChernovMV, GudkovAV. 1999. A chemical inhibitor of p53 that protects mice from the side effects of cancer therapy. Science, 285:1733–1737.
32.
StromE, SatheS, KomarovPG, ChernovaOB, PavlovskaI, ShyshynovaI, BosykhDA, BurdelyaLG, MacklisRMet al.2006. Small-molecule inhibitor of p53 binding to mitochondria protects mice from gamma radiation. Nat Chem Biol, 2:474–479.
33.
ChristopherMJ, RaoM, LiuF, WoloszynekJR, LinkDC. 2011. Expression of the G-CSF receptor in monocytic cells is sufficient to mediate hematopoietic progenitor mobilization by G-CSF in mice. J Exp Med, 208:251–260.
34.
MorrisonSJ, WandyczAM, AkashiK, GlobersonA, WeissmanIL. 1996. The aging of hematopoietic stem cells. Nat Med, 2:1011–1016.
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