The Alchemist's Nightmare Might Mesenchymal St.pdf

May 8,2018 Circulation.2018;137:20682073.DOI:10.1161/CIRCULATIONAHA.117.0321902068Milton Packer,MDABSTRACT:The injection of mesenchymal stem cells into the injured myocardium to induce cardiac regeneration has yielded disappointing results,conceivably because cells with cardioreparative potential must be supplied for long periods of time to produce a salutary effect.Accordingly,investigators have devised ways of directing such cells to the heart on an ongoing basis:by enhancing the action of endogenous peptides that function as cardiac homing signals(eg,stromal cellderived factor1).Stromal cellderived factor1 is released during acute cardiac injury and heart failure,but it has a short half-life because of degradation by dipeptidyl peptidase4.Inhibition of dipeptidyl peptidase4 potentiates the actions of stromal cellderived factor1 and,theoretically,could enhance cardiac recovery.However,in large-scale trials in patients with type 2 diabetes mellitus,dipeptidyl peptidase4 inhibitors have not reduced the risk of atherosclerotic ischemic events,and they have unexpectedly increased the risk of heart failure,most probably heart failure with a preserved ejection fraction.Such an outcome might be explained if the channeling of mesenchymal stem cells to the heart by the actions of stromal cellderived factor1(especially from nearby adipose tissue)were followed by the transformation of these cells into fibroblasts rather than cardiomyocytes.This concern has been supported by experimental studies;the resulting fibrosis would be expected to exacerbate the pathophysiological derangements that lead to heart failure with a preserved ejection fraction.Given the widespread use of dipeptidyl peptidase4 inhibitors,the possibility that these drugs potentiate the cardiac homing of mesenchymal stem cells that cause myocardial fibrosis(rather than repair)warrants further study.2018 American Heart Association,Inc.PRIMERThe Alchemists NightmareMight Mesenchymal Stem Cells That Are Recruited to Repair the Injured Heart Be Transformed Into Fibroblasts Rather Than Cardiomyocytes?http:/circ.ahajournals.orgCirculationKey Words:cardiac regeneration dipeptidyl peptidase-4 inhibitors mesenchymal stem cells stromal cell-derived factor-1 by guest on May 8,2018http:/circ.ahajournals.org/Downloaded from Packer Alchemy,Mesenchymal Stem Cells,and FibrosisSTATE OF THE ARTCirculation.2018;137:20682073.DOI:10.1161/CIRCULATIONAHA.117.032190 May 8,20182069Although alchemy is commonly believed to have been focused entirely on the conversion of base metals into gold,one of its principal goals was the transformation of materials so that they might be used as panaceas to cure any disease to perfect the hu-man body and soul.Its ultimate pursuit was the cre-ation of the philosophers stone,which could heal all forms of illness and prolong the life,revive the dead,and promote the creation of clones.Belief in the funda-mental principles of alchemy persists in medicine in the modern era among researchers who seek to exploit the administration or recruitment of progenitor-type cells(such as mesenchymal stem cells)to promote tissue re-generation.1 In recent years,this alchemists dream has turned its focus to the rejuvenation of hearts in patients with chronic heart failure.RATIONALE FOR CARDIAC HOMING OF MESENCHYMAL STEM CELLSNumerous trials have explored the response to the injection of allogeneic bone marrowderived human mesenchymal stem cells in the hope that these might be transformed into normally contracting cardiomyo-cytes or might act in a paracrine manner to promote the proliferation and adaptive differentiation of resi-dent cells.2,3 Given the invasive nature of this inter-vention and uncertainties about dose,46 interest has shifted to the investigation of treatments that act by augmenting the recruitment of endogenous progeni-tor cells to the heart.Whereas the injection of cells through an interventional catheter typically represents a one-time event,46 the long-term use of drugs that enhance the cardiac homing of circulating or neigh-boring mesenchymal stem cells could provide an on-going supply of cells with reparative potential that could conceivably sustain cardiac regeneration for long periods of time.79If the capacity for regeneration is impaired in heart failure,10 this deficiency could be addressed if physicians were able to channel mesenchymal stem cells to the heart efficiently to foster cardiac rejuvenation.Stromal cellderived factor1(SDF-1)and its cognate receptor CXCR4 play a crucial role in the homing of cells with reparative potential to injured tissue.1113 SDF-1 is up-regulated in acute myocardial infarction,and circulating levels of SDF-1 are increased in chronic heart failure,1417 suggesting that this homing stimulus may already be activated in patients with impaired cardiac function.PHARMACOLOGICAL ENHANCEMENT OF THE CARDIAC HOMING SIGNALDespite its activation,many investigators believe that the magnitude of the existing homing signal for cells that possess the capacity for cardiac repair may be insufficient.Consequently,concerted efforts have been made to enhance the myocardial levels of SDF-1 through the endomyocardial delivery of plasmid-based SDF-1,18,19 generally with disappointing results.Admit-tedly,a major limitation of the therapeutic delivery of SDF-1 is its short plasma half-life that results from its cleavage by dipeptidyl peptidase4(DPP-4).20 Research-ers have endeavored to prolong the duration of the effect of SDF-1 through the use of engineered slow-release systems.21 However,it seems likely that the most effective approach to sustaining the potential of SDF-1 as a means of enhancing endogenous repair is to inhibit the peptides degradation.20,22 Accordingly,in experi-mental myocardial infarction,inhibition of DPP-4 has been utilized as a means of enhancing the actions of endogenous SDF-1,and this strategy has been reported to improve cardiac function and reduce infarct size.22After the resolution of the acute phase of cardiac injury,SDF-1 levels in the heart normally subside,11 lead-ing potentially to a closure of the window of opportu-nity for regeneration.However,in patients with chronic heart failure,the augmentation of SDF-1 persists.Pa-tients with heart failure have increased circulating lev-els of SDF-1,1417 and the expression of the receptor for SDF-1 is upregulated in the failing heart.23 The effec-tiveness of this potentially regenerative homing signal may be limited,however,by the simultaneous increase in the activity of DPP-4 in patients with heart failure24 because DPP-4 can rapidly degrade SDF-1,thus curtail-ing its biological actions.Inhibition of DPP-4 potentiates the actions of endogenous SDF-1,and conceivably,do-ing so might promote cardiac regeneration in patients with chronically impaired hearts.20,22POTENTIATION OF THE CARDIAC HOMING SIGNAL IN LARGE-SCALE TRIALSThe diabetic heart is structurally and functionally abnor-mal,is at risk of further deterioration,and thus might benefit from enhanced repair.Thus,the widespread use of DPP-4 inhibitors as antihyperglycemic agents in pa-tients with type 2 diabetes mellitus provides an oppor-tunity to evaluate the potential of augmenting endog-enous SDF-1 to promote cardiac healing.Interestingly,this hypothesis was inadvertently tested when large-scale cardiovascular outcomes trials with sitagliptin,saxagliptin,and alogliptin were carried out for the pur-poses of evaluating their cardiovascular safety.2527 The 2 trials with sitagliptin and saxagliptin enrolled clinically stable patients without evidence of acute cardiac in-jury at the time of randomization.Therefore,they af-forded an opportunity to explore the consequences of enhanced cardiac homing of mesenchymal stem cells by guest on May 8,2018http:/circ.ahajournals.org/Downloaded from Packer Alchemy,Mesenchymal Stem Cells,and FibrosisSTATE OF THE ARTMay 8,2018 Circulation.2018;137:20682073.DOI:10.1161/CIRCULATIONAHA.117.0321902070in patients whose injury was slow and indolent rather than acute and dramatic.Despite a sustained benefit on glycemic control,treatment with the 3 different DPP-4 inhibitors did not reduce the risk of major adverse cardiovascular events,as assessed by the combined risk of cardiovascular death,nonfatal myocardial infarction,and nonfatal stroke.2527 This lack of benefit stands in marked con-trast with the significant or nearly significant reduction in the risk of atherosclerotic ischemic events reported with liraglutide,semaglutide,and exenatide,2830 which(like DPP-4 inhibitors)enhance signaling through the glucagon-like peptide1 receptor,but(unlike DPP-4 inhibitors)do not potentiate the actions of endoge-nous SDF-1.Signaling through the glucagon-like pep-tide1receptor promotes the stability of atherosclerotic plaques,but this benefit is likely negated with DPP-4 inhibitors because the action of the latter to augment SDF-1 promotes vascular inflammation and increases the likelihood of plaque rupture.31It is important to note that the findings with DPP-4 inhibitors also differ from the effects of SGLT2(sodium-glucose cotransporter 2)inhibitors,which have been shown to decrease the risk of new-onset heart fail-ure in 2 trials.32,33 By comparison,the DPP-4 inhibitors saxagliptin and alogliptin have been associated with an increase in the risk of hospitalization for heart failure in their respective large-scale cardiovascular outcomes studies.26,27 Meta-analyses of randomized trials and ob-servational studies have reinforced concerns that long-term therapy with DPP-4 inhibitors can adversely affect the clinical course of patients with type 2 diabetes mel-litus who are at risk of developing heart failure during follow-up.34,35 Postmarketing analyses by the US Food and Drug Administration have noted a disproportionate reporting of adverse heart failure events among users of all members of the drug class.36UNINTENDED CONSEQUENCES OF CARDIAC HOMING POTENTIATIONWhat mechanism might underlie the increased risk of heart failure with DPP-4 inhibitors in patients with type 2 diabetes mellitus?Although the heart failure phe-notype in the trials of DPP-4 inhibitors was not well characterized,patients with diabetes mellitus are more likely to develop heart failure associated with a pre-served ejection fraction rather than a reduced ejection fraction.3740 The major pathophysiological abnormality in heart failure with a preserved ejection fraction is not a critical loss of contracting cardiomyocytes but a lack of ventricular distensibility that is related to myocardial inflammation,microcirculatory rarefaction,and cardiac fibrosis.41,42 In the diabetic heart and other states that are characterized by enhanced cardiac stiffness,fibrosis appears to be related to increased SDF-1 signaling.43,44 Potentiation of the interaction of SDF-1 with its recep-tor can promote both inflammation and fibroblast pro-liferation and can adversely affect cardiac remodeling and ventricular function.4547 It is therefore interesting that,when compared with their counterparts with a reduced ejection fraction,levels of SDF-1 in patients with heart failure and a preserved ejection fraction are not particularly increased.1417 The modest elevation of the chemokine may be related to an impaired release of SDF-1 in patients with multiple comorbidities48 or an increase in the DPP-4 activity,24 which is particularly evident in heart failure with a preserved ejection frac-tion.49,50 However,potentiation of SDF-1 signaling by DPP-4 inhibitors could inadvertently unleash this muted response and aggravate cardiac fibrosis and ventricular stiffness and thereby exacerbate the syndrome of heart failure.51,52How does augmented SDF-1 signaling promote pro-fibrotic processes in the myocardium?During embry-onic development,fibroblasts are typically derived from cells residing in the proepicardium,53,54 but after experi-mental myocardial infarction,scar formation appears to involve cells that originate from resident fibroblasts.54,55 However,these studies of experimental infarction do not address the possibility that pathological fibrosis in noninfarcted hearts may involve interaction with mes-enchymal stem cells that are recruited into the region of injury,53 a process that is enhanced by an increase in the activity of SDF-1.5560 Despite work suggesting that migrating cells originate in the bone marrow,61 in mod-els of noninfarction cardiac fibrosis,new fibroblasts ap-pear to originate from mesenchymal stem cells in the epicardium,57,62 particularly those derived from adjacent epicardial adipose tissue.63,64 The accumulation and in-flammation of epicardial fat is a characteristic feature of heart failure with a preserved ejection fraction and has been linked to underlying cardiac fibrosis,6567 possibly because it serves as a source of migratory mesenchymal stem cells.68 Left ventricular dysfunction also switches mesenchymal stromal cells toward an inflammatory phenotype and impairs their reparative properties.69 Re-gardless of their source,the mesenchymal stem cells are not transformed into cardiomyocytes68 and may be transformed in fibroblasts.55,70 A recent consensus statement emphasizes that cardiomyocyte regeneration does not result from progenitor cells supplied from ex-tracardiac sources.68It is noteworthy that patients with type 2 diabetes mellitus may be particularly susceptible to the deleteri-ous actions of SDF-1 on the heart.Hyperglycemia in-creases the release of SDF-1 and activates CXCR4(the receptor for SDF-1).71,72 Antagonism of CXCR4(and thus the actions of SDF-1)can attenuate cardiac fibrosis in experimental models of diabetes mellitus and other states where ventricular overfilling and impaired disten-by guest on May 8,2018http:/circ.ahajournals.org/Downloaded from Packer Alchemy,Mesenchymal Stem Cells,and FibrosisSTATE OF THE ARTCirculation.2018;137:20682073.DOI:10.1161/CIRCULATIONAHA.117.032190 May 8,20182071sibility are prominent.43,44 Conversely,DPP-4 inhibition augments SDF-1 signaling and thus would be expected to exacerbate myocardial fibrosis and cardiac stiffness,particularly in diabetes mellitus.51CONCLUSIONSCould long-term potentiation of SDF-1 by DPP-4 in-hibitors in patients with type 2 diabetes mellitus pro-mote cardiac inflammation and fibrosis and increase the likelihood of developing heart failure with a pre-served ejection fraction?Could the ongoing augmen-tation of the homing of mesenchymal stem cells to the chronically stressed diabetic heart lead to the mi-gration of cells that are transformed into fibroblasts rather than cardiomyocytes?These possibilities have been raised by the findings that DPP-4 inhibitors might increase the risk of new-onset heart failure in patients with diabetes mellitus even in the absence of an interval ischemic event.26 The process of mal-adaptive fibrosis might become particularly important after long periods of treatment,which may exceed the median duration of the large-scale card