Use of Statins to Augment Progenitor Cell Function in Preclinical and Clinical Studies of Regenerative Therapy: a Systematic Review

Park, Angela; Barrera‐Ramirez, Juliana; Ranasinghe, Indee; Pilon, Sophie; Sy, Richmond; Fergusson, Dean; Allan, David S.

doi:10.1007/s12015-016-9647-7

Cited by 29 publications

(19 citation statements)

References 71 publications

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“…In particular, statins are shown to be effective against A. actinomycetemcomitans and Porphyromonas gingivalis , 2 of the major species of bacteria implicated in periodontitis pathogenesis. Furthermore, statins are shown to inhibit tissue‐degrading enzymes (i.e., matrix metalloproteinases) and to exert a pro‐proliferative effect on mesenchymal stromal cells and endothelial progenitor cells . Statins are also shown to enhance osteoblastic differentiation and viability, bone morphogenetic protein and vascular endothelial growth factor expression and to interfere with bone resorption and osteoclastogenesis …”

Section: Discussionmentioning

confidence: 99%

“…Statins present high efficacy and tolerability in general, are rather inexpensive and by inhibiting cholesterol synthesis reduce the risk for cardiovascular diseases . Besides reducing cholesterol levels, statins have also been shown to possess antimicrobial, antiviral, fungicidal, anti‐inflammatory and pro‐osteogenic properties and to enhance the number and/or function of mesenchymal stromal cells and/or endothelial progenitor cells; thus, statins appear relevant in periodontology, either in preventing disease or in periodontal therapy.…”

Section: Introductionmentioning

confidence: 99%

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Statins in nonsurgical and surgical periodontal therapy. A systematic review and meta‐analysis of preclinical in vivo trials

Bertl

Steiner

Pandis

et al. 2017

J of Periodontal Research

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The cholesterol-lowering drugs, statins, possess anti-inflammatory, antimicrobial and pro-osteogenic properties, and thus have been tested as an adjunct to periodontal treatment. The present systematic review aimed to answer the following focused research question: What is the effect of local and/or systemic statin use on periodontal tissues in preclinical in vivo studies of experimentally induced periodontitis (EIP) and/or acute/chronified periodontal defect (ACP) models? A literature search (of Medline/PubMed, Embase/Ovid, CENTRAL/Ovid) using the following main eligibility criteria was performed: (i) English or German language; (ii) controlled preclinical in vivo trials; (iii) local and/or systemic statin use in EIP and/or ACP models; and (iv) quantitative evaluation of periodontal tissues (i.e., alveolar bone level/amount, attachment level, cementum formation, periodontal ligament formation). Sixteen studies in EIP models and 7 studies in ACP models evaluated simvastatin, atorvastatin or rosuvastatin. Thirteen of the EIP (81%) and 2 of the ACP (29%) studies presented significantly better results in terms of alveolar bone level/amount in favor of statins. Meta-analysis based on 14 EIP trials confirmed a significant benefit of local and systemic statin use (P < .001) in terms of alveolar bone level/amount; meta-regression revealed that statin type exhibited a significant effect (P = .014) in favor of atorvastatin. Three studies reported a significantly higher periodontal attachment level in favor of statin use (P < .001). Complete periodontal regeneration was never observed; furthermore, statins did not exert any apparent effect on cementum formation. Neither local nor systemic use of statins resulted in severe adverse effects. Statin use in periodontal indications has a positive effect on periodontal tissue parameters, supporting the positive results already observed in clinical trials. Nevertheless, not all statins available have been tested so far, and further research is needed to identify the maximum effective concentration/dose and optimal carrier.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Statins in nonsurgical and surgical periodontal therapy. A systematic review and meta‐analysis of preclinical in vivo trials

Bertl

Steiner

Pandis

et al. 2017

J of Periodontal Research

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“…Also, ex vivo statin treatment has been shown to prevent impairment of the functionality of EPCs in vitro as well as the loss of telomere repeat-binding factor 2, whose expression is reduced in end-stage human HF, and functions to prevent cells from entering in apoptosis or senescence[149,150]. A recent review provides encouraging basis for the use of statins to increase the number and/or function of MSCs and EPCs for cell therapy[151]. …”

Section: Preconditioning Stem Cells With Drugsmentioning

confidence: 99%

Optimizing stem cells for cardiac repair: Current status and new frontiers in regenerative cardiology

Sarkissian¹,

Lévesque²,

Noiseux³

2017

WJSC

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Cell therapy has the potential to improve healing of ischemic heart, repopulate injured myocardium and restore cardiac function. The tremendous hope and potential of stem cell therapy is well understood, yet recent trials involving cell therapy for cardiovascular diseases have yielded mixed results with inconsistent data thereby readdressing controversies and unresolved questions regarding stem cell efficacy for ischemic cardiac disease treatment. These controversies are believed to arise by the lack of uniformity of the clinical trial methodologies, uncertainty regarding the underlying reparative mechanisms of stem cells, questions concerning the most appropriate cell population to use, the proper delivery method and timing in relation to the moment of infarction, as well as the poor stem cell survival and engraftment especially in a diseased microenvironment which is collectively acknowledged as a major hindrance to any form of cell therapy. Indeed, the microenvironment of the failing heart exhibits pathological hypoxic, oxidative and inflammatory stressors impairing the survival of transplanted cells. Therefore, in order to observe any significant therapeutic benefit there is a need to increase resilience of stem cells to death in the transplant microenvironment while preserving or better yet improving their reparative functionality. Although stem cell differentiation into cardiomyocytes has been observed in some instance, the prevailing reparative benefits are afforded through paracrine mechanisms that promote angiogenesis, cell survival, transdifferentiate host cells and modulate immune responses. Therefore, to maximize their reparative functionality, ex vivo manipulation of stem cells through physical, genetic and pharmacological means have shown promise to enable cells to thrive in the post-ischemic transplant microenvironment. In the present work, we will overview the current status of stem cell therapy for ischemic heart disease, discuss the most recurring cell populations employed, the mechanisms by which stem cells deliver a therapeutic benefit and strategies that have been used to optimize and increase survival and functionality of stem cells including ex vivo preconditioning with drugs and a novel “pharmaco-optimizer” as well as genetic modifications.

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“…Conversely, Deschaseaux et al found that the number of EPC colonies after 5 days of culture was lower in patients on chronic statin treatment (here with 40 mg/day of pravastatin or simvastatin for at least 4 weeks) compared with those without statin therapy, while long-term statin treatment would preserve late EPC colonies [54]. Recently, a systematic review of preclinical and clinical studies on statin and EPCs [55] reported two clinical studies examining the effect of statin therapy on EPC levels in CAD patients [56, 57]. One study used atorvastatin and the other used rosuvastatin.…”

Section: Discussionmentioning

confidence: 99%

The acute impact of high-dose lipid-lowering treatment on endothelial progenitor cells in patients with coronary artery disease—The REMEDY-EPC early substudy

et al. 2017

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Rationale and objectiveEndothelial progenitor cells (EPCs) play a role in vascular repair, while circulating endothelial cells (CECs) are biomarkers of vascular damage and regeneration. Statins may promote EPC/CEC mobilization in the peripheral blood. We evaluated whether pre-procedural exposure to different lipid-lowering drugs (statins±ezetimibe) can acutely increase levels/activity of EPCs/CECs in patients with stable coronary artery disease (CAD).MethodsIn a planned sub-analysis of the Rosuvastatin For REduction Of Myocardial DamagE During Coronary AngioplastY (REMEDY) trial, 38 patients with stable CAD on chronic low-dose statin therapy were randomized, in a double-blind, placebo-controlled design, into 4 groups before PCI: i. placebo (n = 11); ii. atorvastatin (80 mg+40 mg, n = 9); iii. rosuvastatin (40 mg twice, n = 9); and iv. rosuvastatin (5 mg) and ezetimibe (10 mg) twice, (n = 9). At baseline and 24 h after treatment–before PCI–, patients underwent blinded analyses of EPCs [colony forming units-endothelial cells (CFU-ECs), endothelial colony-forming cells (ECFCs) and tubulization activity] and CECs in peripheral blood.ResultsWe found no significant treatment effects on parameters investigated such as number of CECs [Median (IQR): i. 0(0), ii. 4.5(27), iii. 1.9(2.3), iv. 1.9(2.3)], CFU-ECs [Median (IQR): i. 27(11), ii. 19(31), iii. 47(36), iv. 30(98)], and ECFCs [Median (IQR): i. 86(84), ii. 7(84), iii. 8/(42.5), iv. 5(2)], as well as tubulization activity [total tubuli (well), Median (IQR): i. 19(7), ii. 5(4), iii. 25(13), iv. 15(24)].ConclusionsIn this study, we found no evidence of acute changes in levels or activity of EPCs and CECs after high-dose lipid-lowering therapy in stable CAD patients.

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Use of Statins to Augment Progenitor Cell Function in Preclinical and Clinical Studies of Regenerative Therapy: a Systematic Review

Cited by 29 publications

References 71 publications

Statins in nonsurgical and surgical periodontal therapy. A systematic review and meta‐analysis of preclinical in vivo trials

Statins in nonsurgical and surgical periodontal therapy. A systematic review and meta‐analysis of preclinical in vivo trials

Optimizing stem cells for cardiac repair: Current status and new frontiers in regenerative cardiology

The acute impact of high-dose lipid-lowering treatment on endothelial progenitor cells in patients with coronary artery disease—The REMEDY-EPC early substudy

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