SDF-1:CXCR4 Axis Is Fundamental for Tissue Preservation and Repair
2010; Elsevier BV; Volume: 177; Issue: 5 Linguagem: Inglês
10.2353/ajpath.2010.100803
ISSN1525-2191
Autores Tópico(s)Tissue Engineering and Regenerative Medicine
ResumoThis Commentary discusses the role of the SDF-1:CXCR4 axis in tissue preservation and repair. This Commentary discusses the role of the SDF-1:CXCR4 axis in tissue preservation and repair. Adult stem cell therapy has demonstrated the potential for tissue preservation and repair in multiple organ systems including the heart,1Schächinger V Erbs S Elsasser A Haberbosch W Hambrecht R Holschermann H Yu J Corti R Mathey DG Hamm CW Suselbeck T Assmus B Tonn T Dimmeler S Zeiher AM Intracoronary bone marrow-derived progenitor cells in acute myocardial infarction.N Engl J Med. 2006; 355: 1210-1221Crossref PubMed Scopus (1682) Google Scholar liver,2Vassilopoulos G Wang PR Russell DW Transplanted bone marrow regenerates liver by cell fusion.Nature. 2003; 422: 901-904Crossref PubMed Scopus (1175) Google Scholar brain,3Nakano-Doi A Nakagomi T Fujikawa M Nakagomi N Kubo S Lu S Yoshikawa H Soma T Taguchi A Matsuyama T Bone marrow mononuclear cells promote proliferation of endogenous neural stem cells through vascular niches after cerebral infarction.Stem Cells. 2010; 28: 1292-1302PubMed Google Scholar skin,4Snippert HJ Haegebarth A Kasper M Jaks V van Es JH Barker N van de Wetering M van den Born M Begthel H Vries RG Stange DE Toftgard R Clevers H Lgr6 marks stem cells in the hair follicle that generate all cell lineages of the skin.Science. 2010; 327: 1385-1389Crossref PubMed Scopus (578) Google Scholar and kidney.5Choi SJ Kim JK Hwang SD Mesenchymal stem cell therapy for chronic renal failure.Expert Opin Biol Ther. 2010; 10: 1217-1226Crossref PubMed Scopus (38) Google Scholar In some organ systems, such as the liver, there is evidence of real regeneration,6Lagasse E Connors H Al Dhalimy M Reitsma M Dohse M Osborne L Wang X Finegold M Weissman IL Grompe M Purified hematopoietic stem cells can differentiate into hepatocytes in vivo.Nat Med. 2000; 6: 1229-1234Crossref PubMed Scopus (2137) Google Scholar whereas in other organ systems, such as the heart, there is little evidence for tissue regeneration.7Murry CE Soonpaa MH Reinecke H Nakajima H Nakajima HO Rubart M Pasumarthi KB Virag JI Bartelmez SH Poppa V Bradford G Dowell JD Williams DA Field LJ Haematopoietic stem cells do not transdifferentiate into cardiac myocytes in myocardial infarcts.Nature. 2004; 428: 664-668Crossref PubMed Scopus (1909) Google Scholar, 8Zhang M Mal N Kiedrowski M Chacko M Askari AT Popovic ZB Koc ON Penn MS SDF-1 expression by mesenchymal stem cells results in trophic support of cardiac myocytes after myocardial infarction.FASEB J. 2007; 21: 3197-3207Crossref PubMed Scopus (395) Google Scholar Regardless of whether tissue is regenerated in a given organ system, consistent evidence exists across all organ systems for modulation of cell death, leading to preservation of organ-specific tissue function. The similarity of tissue preservation across systems suggests that there may exist a common mechanism of use for adult stem cell therapy; furthermore, the findings that conditioned media from adult stem cells led to tissue preservation suggested that the effect was due, at least in part, to paracrine factor expression by the adult stem cells.8Zhang M Mal N Kiedrowski M Chacko M Askari AT Popovic ZB Koc ON Penn MS SDF-1 expression by mesenchymal stem cells results in trophic support of cardiac myocytes after myocardial infarction.FASEB J. 2007; 21: 3197-3207Crossref PubMed Scopus (395) Google Scholar, 9Gnecchi M Zhang Z Ni A Dzau VJ Paracrine mechanisms in adult stem cell signaling and therapy.Circ Res. 2008; 103: 1204-1219Crossref PubMed Scopus (1602) Google Scholar Early in the investigation of the mechanisms related to stem cell-based tissue repair, the stromal cell-derived factor-1 (SDF-1):CXCR4 axis was identified as a key factor in the recruitment of stem cells to areas of tissue injury in multiple organ systems.10Askari A Unzek S Popovic ZB Goldman CK Forudi F Kiedrowski M Rovner A Ellis SG Thomas JD DiCorleto PE Topol EJ Penn MS Effect of stromal-cell-derived factor-1 on stem cell homing and tissue regeneration in ischemic cardiomyopathy.Lancet. 2003; 362: 697-703Abstract Full Text Full Text PDF PubMed Scopus (1122) Google Scholar, 11Rosenkranz K Kumbruch S Lebermann K Marschner K Jensen A Dermietzel R Meier C The chemokine SDF-1/CXCL12 contributes to the ‘homing’ of umbilical cord blood cells to a hypoxic-ischemic lesion in the rat brain.J Neurosci Res. 2010; 88: 1223-1233PubMed Google Scholar, 12Stokman G Stroo I Claessen N Teske GJ Florquin S Leemans JC SDF-1 provides morphological and functional protection against renal ischaemia/reperfusion injury.Nephrol Dial Transplant. 2010; https://doi.org/10.1093/ndt/gfq311Crossref PubMed Scopus (53) Google Scholar These findings led us to propose that the reestablishment of SDF-1 expression late after tissue injury could serve as a strategy to induce tissue repair;10Askari A Unzek S Popovic ZB Goldman CK Forudi F Kiedrowski M Rovner A Ellis SG Thomas JD DiCorleto PE Topol EJ Penn MS Effect of stromal-cell-derived factor-1 on stem cell homing and tissue regeneration in ischemic cardiomyopathy.Lancet. 2003; 362: 697-703Abstract Full Text Full Text PDF PubMed Scopus (1122) Google Scholar, 13Deglurkar I Mal N Mills WR Popovic ZB McCarthy P Blackstone EH laurita KR Penn MS Mechanical and electrical effects of cell-based gene therapy for ischemic cardiomyopathy are independent.Hum Gene Ther. 2006; 17: 1144-1151Crossref PubMed Scopus (42) Google Scholar this hypothesis is now the focus of an on-going clinical trial in patients with chronic heart failure (NCT01082094, clinicaltrials.gov). More recently, studies by our group and others have demonstrated that the expression of SDF-1 at the time of acute injury induces the recruitment of endogenous tissue-specific stem cells14Unzek S Zhang M Mal N Mills WR Laurita KR Penn MS SDF-1 recruits cardiac stem cell like cells that depolarize in vivo.Cell Transplant. 2007; 16: 879-886Crossref PubMed Scopus (74) Google Scholar as well as direct preservation of end-organ cells such as cardiac myocytes.8Zhang M Mal N Kiedrowski M Chacko M Askari AT Popovic ZB Koc ON Penn MS SDF-1 expression by mesenchymal stem cells results in trophic support of cardiac myocytes after myocardial infarction.FASEB J. 2007; 21: 3197-3207Crossref PubMed Scopus (395) Google Scholar Further demonstrating the importance of the SDF-1 in tissue repair, in this issue of the journal, Otsuka et al15Otsuka H Arimura N Sonoda S Nakamura M Hashiguchi T Maruyama I Nakao S Hafezi-Moghadam A Sakamoto T Stromal cell-derived factor-1 is essential for photoreceptor cell protection in retinal detachment.Am J Pathol. 2010; 177: 2268-2277Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar demonstrate the role of SDF-1 in inhibiting photoreceptor cell loss in retinal detachment. These investigators quantified the levels of vascular endothelial growth factor and SDF-1 in the vitreous of patients with retinal detachment (RD) and proliferative diabetic retinopathy as well as other pathologies. Vascular endothelial growth factor and SDF-1 levels are increased in proliferative diabetic retinopathy;16Djuric Z Sharei V Rudofsky G Morcos M Li H Hammes HP Nawroth PP Bierhaus A Humpert PM Jonas JB Association of homozygous SDF-1 3′A genotype with proliferative diabetic retinopathy.Acta Diabetol. 2010; 47: 79-82Crossref PubMed Scopus (11) Google Scholar, 17Madlambayan GJ Butler JM Hosaka K Jorgensen M Fu D Guthrie SM Shenoy AK Brank A Russell KJ Otero J Siemann DW Scott EW Cogle CR Bone marrow stem and progenitor cell contribution to neovasculogenesis is dependent on model system with SDF-1 as a permissive trigger.Blood. 2009; 114: 4310-4319Crossref PubMed Scopus (50) Google Scholar however, only SDF-1 levels were increased in RD. Interestingly, the up-regulation of SDF-1 in RD did not lead to proliferation of the vasculature of the retina. Consistent with the up-regulation of SDF-1 in response to RD is the correlation of vitreous SDF-1 levels with the extent and duration of RD. The investigators took their observation of increased SDF-1 in the vitreous of patients with RD and nicely investigated the effects of SDF-1 in the R28 retinal precursor cell line and a rat model of RD. Their data demonstrate that there is minimal SDF-1 expression in the normal eye but that within 3 days of experimentally induced RD there is increased SDF-1 expression in the anti-glial fibrillary acidic protein-positive astrocytes. Based on the known biology of the SDF-1, the increased expression of SDF-1 in the vitreous could have multiple effects including recruitment of bone marrow-derived stem cells and local inhibition of cell death in CXCR4-expressing cells. The lack of vascular changes associated with increased SDF-1 expression in patients with RD suggests that SDF-1 expression is not associated with significant recruitment of bone marrow-derived endothelial progenitor cells because it is associated with SDF-1-mediated myocardial healing.8Zhang M Mal N Kiedrowski M Chacko M Askari AT Popovic ZB Koc ON Penn MS SDF-1 expression by mesenchymal stem cells results in trophic support of cardiac myocytes after myocardial infarction.FASEB J. 2007; 21: 3197-3207Crossref PubMed Scopus (395) Google Scholar, 10Askari A Unzek S Popovic ZB Goldman CK Forudi F Kiedrowski M Rovner A Ellis SG Thomas JD DiCorleto PE Topol EJ Penn MS Effect of stromal-cell-derived factor-1 on stem cell homing and tissue regeneration in ischemic cardiomyopathy.Lancet. 2003; 362: 697-703Abstract Full Text Full Text PDF PubMed Scopus (1122) Google Scholar Rather, the mechanism of SDF-1-mediated healing or tissue preservation in the eye seems to be more related to that seen in the skin, the healing of which is also not associated with vascular growth.18Rabbany SY Pastore J Yamamoto M Miller T Rafii S Aras R Penn MS Continuous delivery of stromal cell-derived factor-1 from alginate scaffolds accelerates wound healing.Cell Transplant. 2010; 19: 399-408Crossref PubMed Scopus (126) Google Scholar Otsuka et al15Otsuka H Arimura N Sonoda S Nakamura M Hashiguchi T Maruyama I Nakao S Hafezi-Moghadam A Sakamoto T Stromal cell-derived factor-1 is essential for photoreceptor cell protection in retinal detachment.Am J Pathol. 2010; 177: 2268-2277Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar demonstrate that SDF-1 expression in the eye in the setting of RD is associated with preservation of photoreceptors in the outer nuclear layer. Further demonstrating that the effects of SDF-1 are specific in response to injury, inhibition of SDF-1 signaling in the normal eye had no effects on cells in the outer nuclear layer. Of importance, the specificity of the SDF-1 response was mediated by the expression of CXCR4 by photoreceptors in the outer nuclear layer. CXCR4 expression in the normal retina was limited to the ganglion cell and the inner nuclear layers; however, in response to RD, there was significant CXCR4 expression in the outer nuclear layer and photoreceptor inner segments of the detached retina. The importance of the SDF-1:CXCR4 axis on cell survival was confirmed in studies using the R28 retinal precursor cell line in the setting of serum starvation, similar to what we have previously demonstrated in the setting of hypoxia and serum starvation using mesenchymal stem cells.8Zhang M Mal N Kiedrowski M Chacko M Askari AT Popovic ZB Koc ON Penn MS SDF-1 expression by mesenchymal stem cells results in trophic support of cardiac myocytes after myocardial infarction.FASEB J. 2007; 21: 3197-3207Crossref PubMed Scopus (395) Google Scholar Perhaps directly in the eye15Otsuka H Arimura N Sonoda S Nakamura M Hashiguchi T Maruyama I Nakao S Hafezi-Moghadam A Sakamoto T Stromal cell-derived factor-1 is essential for photoreceptor cell protection in retinal detachment.Am J Pathol. 2010; 177: 2268-2277Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar and skin18Rabbany SY Pastore J Yamamoto M Miller T Rafii S Aras R Penn MS Continuous delivery of stromal cell-derived factor-1 from alginate scaffolds accelerates wound healing.Cell Transplant. 2010; 19: 399-408Crossref PubMed Scopus (126) Google Scholar and more circuitously in other organ systems including the heart10Askari A Unzek S Popovic ZB Goldman CK Forudi F Kiedrowski M Rovner A Ellis SG Thomas JD DiCorleto PE Topol EJ Penn MS Effect of stromal-cell-derived factor-1 on stem cell homing and tissue regeneration in ischemic cardiomyopathy.Lancet. 2003; 362: 697-703Abstract Full Text Full Text PDF PubMed Scopus (1122) Google Scholar and brain,19Wang F Yasuhara T Shingo T Kameda M Tajiri N Yuan WJ Kondo A Kadota T Baba T Tayra JT Kikuchi Y Miyoshi Y Date I Intravenous administration of mesenchymal stem cells exerts therapeutic effects on parkinsonian model of rats: focusing on neuroprotective effects of stromal cell-derived factor-1alpha.BMC Neurosci. 2010; 11: 52-60Crossref PubMed Scopus (124) Google Scholar up-regulation of the SDF-1:CXCR4 axis is a fundamental response to tissue injury and modulating SDF-18Zhang M Mal N Kiedrowski M Chacko M Askari AT Popovic ZB Koc ON Penn MS SDF-1 expression by mesenchymal stem cells results in trophic support of cardiac myocytes after myocardial infarction.FASEB J. 2007; 21: 3197-3207Crossref PubMed Scopus (395) Google Scholar and CXCR420Tang YL Zhu W Cheng M Chen L Zhang J Sun T Kishore R Phillips MI Losordo DW Qin G Hypoxic preconditioning enhances the benefit of cardiac progenitor-cell therapy for treatment of myocardial infarction by inducing CXCR4 expression.Circ Res. 2009; 104: 1209-1216Crossref PubMed Scopus (307) Google Scholar expression can serve as a strategy to preserve and restore end-organ function. The sequence of events after tissue injury is generalized in Figure 1: i) After tissue injury there is a local up-regulation of SDF-1 expression. The increased SDF-1 expression leads to homing of endogenous and bone marrow-derived stem cells in some organ system. ii) The end-organ cells up-regulate CXCR4 expression. The local up-regulation of CXCR4 can lead to cellular dysfunction21Pyo RT Sui J Dhume A Palomeque J Blaxall BC Diaz G Tunstead J Logothetis DE Hajjar RJ Schecter AD CXCR4 modulates contractility in adult cardiac myocytes.J Mol Cell Cardiol. 2006; 41: 834-844Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar but renders the cell responsive to SDF-1-mediated survival. As delineated in Figure 1, the up-regulation of SDF-1 can lead to stem cell homing and engraftment that seems to be associated with neovascularization. In the absence of stem cell homing as seen in this study by Otsuka et al15Otsuka H Arimura N Sonoda S Nakamura M Hashiguchi T Maruyama I Nakao S Hafezi-Moghadam A Sakamoto T Stromal cell-derived factor-1 is essential for photoreceptor cell protection in retinal detachment.Am J Pathol. 2010; 177: 2268-2277Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar and in recent studies on SDF-1-mediated surgical wound healing,18Rabbany SY Pastore J Yamamoto M Miller T Rafii S Aras R Penn MS Continuous delivery of stromal cell-derived factor-1 from alginate scaffolds accelerates wound healing.Cell Transplant. 2010; 19: 399-408Crossref PubMed Scopus (126) Google Scholar SDF-1 expression does not seem to induce neovascularization. One recurring question regarding the importance of the SDF-1:CXCR4 axis in tissue repair is if the axis is so critical, why does the up-regulation of CXCR4 on end-organ cells often occur at a time when SDF-1 expression is declining22Penn MS Importance of the SDF-1: CXCR4 axis in myocardial repair.Circ Res. 2009; 104: 1133-1135Crossref PubMed Scopus (103) Google Scholar? We have recently demonstrated that although SDF-1:CXCR4 coexpression is required for normal cardiac development,23Nelson TJ Faustino RS Chiriac A Crespo-Diaz R Behfar A Terzic A CXCR4+/FLK-1+ biomarkers select a cardiopoietic lineage from embryonic stem cells.Stem Cells. 2008; 26: 1464-1473Crossref PubMed Scopus (93) Google Scholar once cardiac myocyte fate is determined, CXCR4 expression is no longer required.24Agarwal U Ghalayini W Dong F Weber K Zou YR Rabbany SY Rafii S Penn MS Role of cardiac myocyte CXCR4 expression in development and left ventricular remodeling after acute myocardial infarction.Circ Res. 2010; (doi: 0.1161/CIRCRESAHA.110.223289)PubMed Google Scholar Thus, one hypothesis is that because SDF-1:CXCR4 expression is intimately involved in tumor metastases,25Lee HJ Kim SW Kim HY Li S Yun HJ Song KS Kim S Jo DY Chemokine receptor CXCR4 expression, function, and clinical implications in gastric cancer.Int J Oncol. 2009; 34: 473-480PubMed Google Scholar, 26Richert MM Vaidya KS Mills CN Wong D Korz W Hurst DR Welch DR Inhibition of CXCR4 by CTCE-9908 inhibits breast cancer metastasis to lung and bone.Oncol Rep. 2009; 21: 761-767PubMed Google Scholar evolution has favored mammals that, in adulthood, have SDF-1 expression temporally misaligned with organ CXCR4 expression. The study of Otsuka et al15Otsuka H Arimura N Sonoda S Nakamura M Hashiguchi T Maruyama I Nakao S Hafezi-Moghadam A Sakamoto T Stromal cell-derived factor-1 is essential for photoreceptor cell protection in retinal detachment.Am J Pathol. 2010; 177: 2268-2277Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar extends the end-organ systems involved in SDF-1:CXCR4 tissue preservation and repair. It also raises some important and interesting questions for future studies. In particular, the eye in response to RD, like the bone marrow, seems to have sustained SDF-1 expression. In most organ systems studied to date, SDF-1 is rapidly up- and then down-regulated.22Penn MS Importance of the SDF-1: CXCR4 axis in myocardial repair.Circ Res. 2009; 104: 1133-1135Crossref PubMed Scopus (103) Google Scholar Previous studies have suggested that SDF-1 expression in stroke and myocardial infarction is due to modulation of intracellular hypoxia-inducible factor-1α.20Tang YL Zhu W Cheng M Chen L Zhang J Sun T Kishore R Phillips MI Losordo DW Qin G Hypoxic preconditioning enhances the benefit of cardiac progenitor-cell therapy for treatment of myocardial infarction by inducing CXCR4 expression.Circ Res. 2009; 104: 1209-1216Crossref PubMed Scopus (307) Google Scholar The lack of vascular endothelial growth factor expression in the vitreous of RD suggests that hypoxia-inducible factor-1α is not responsible for SDF-1-mediated expression in RD. Thus, the mechanism of SDF-1 up-regulation in RD remains to be elucidated. In summary, the study by Otsuka et al15Otsuka H Arimura N Sonoda S Nakamura M Hashiguchi T Maruyama I Nakao S Hafezi-Moghadam A Sakamoto T Stromal cell-derived factor-1 is essential for photoreceptor cell protection in retinal detachment.Am J Pathol. 2010; 177: 2268-2277Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar elucidates an important role for SDF-1 expression in preservation of photoreceptors and the outer nuclear layer of the eye after retinal detachment. These findings suggest that CXCR4 expression in the eye is modulated in injury and that exogenous SDF-1 delivery may serve as a strategy to further preserve tissue structure during healing. Future studies need to be focused not only on the therapeutic potential of SDF-1 in ocular disease states but also on the molecular mechanisms associated with SDF-1 up-regulation in the eye after retinal detachment as well as the mechanisms associated with specific CXCR4 expression in specific tissue layers of the eye. Stromal Cell-Derived Factor-1 Is Essential for Photoreceptor Cell Protection in Retinal DetachmentThe American Journal of PathologyVol. 177Issue 5PreviewStromal cell-derived factor-1 (SDF-1) causes chemotaxis of CXCR4-expressing bone marrow-derived cells. SDF-1 is involved in the pathogenesis of various vascular diseases, including those of the eye. However, the role of SDF-1 in neuronal diseases is not completely understood. Here, we show higher SDF-1 levels in the vitreous humor of patients with retinal detachment (RD) compared with normal patients. SDF-1 correlated positively with the duration as well as the extent of RD. Furthermore, SDF-1 correlated significantly with levels of interleukin-6 and interleukin-8, but not with vascular endothelial growth factor. Full-Text PDF Open Archive
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