Increased fibrosis and progression to heart failure in MRL mice following ischemia/reperfusion injury

Smiley, Dia; Smith, Margaret A.; Carreira, Vinicius; Jiang, Min; Koch, Sheryl E.; Kelley, Melissa; Rubinstein, Jack; Jones, W. Keith; Tranter, Michael

doi:10.1016/j.carpath.2014.06.001

Cited by 22 publications

(16 citation statements)

References 32 publications

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“…Since function is the gold standard by which tendon healing is frequently assessed, our finding of improved neonatal tendon function is exciting and comparable to other existing regenerative tendon models, such as MRL/MpJ (and related mouse strains) and fetal sheep, which also recover functional properties after injury5455565758. Although MRL/MpJ and related strains are useful models of adult regeneration in specific contexts, a few recent studies in non-tendon tissues suggest that MRL/MpJ may exhibit accelerated wound closure via excessive scar formation rather than true regeneration59606162. The fetal model on the other hand is technically challenging in mice given the small size and inaccessibility of mouse embryos.…”

Section: Discussionmentioning

confidence: 53%

Novel Model of Tendon Regeneration Reveals Distinct Cell Mechanisms Underlying Regenerative and Fibrotic Tendon Healing

Howell

Chien

Bell

et al. 2017

Sci Rep

217

324

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To date, the cell and molecular mechanisms regulating tendon healing are poorly understood. Here, we establish a novel model of tendon regeneration using neonatal mice and show that neonates heal via formation of a ‘neo-tendon’ that differentiates along the tendon specific lineage with functional restoration of gait and mechanical properties. In contrast, adults heal via fibrovascular scar, aberrant differentiation toward cartilage and bone, with persistently impaired function. Lineage tracing identified intrinsic recruitment of Scx-lineage cells as a key cellular mechanism of neonatal healing that is absent in adults. Instead, adult Scx-lineage tenocytes are not recruited into the defect but transdifferentiate into ectopic cartilage; in the absence of tenogenic cells, extrinsic αSMA-expressing cells persist to form a permanent scar. Collectively, these results establish an exciting model of tendon regeneration and uncover a novel cellular mechanism underlying regenerative vs non-regenerative tendon healing.

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Section: Discussionmentioning

confidence: 53%

Novel Model of Tendon Regeneration Reveals Distinct Cell Mechanisms Underlying Regenerative and Fibrotic Tendon Healing

Howell

Chien

Bell

et al. 2017

Sci Rep

217

324

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“…Chronic endothelial cell perturbation and activation induced by ischemia/reperfusion lead to dysfunction and irreversible loss of integrity, with cell detachment and tissue injury. In mice, increased fibrosis and progression to heart failure was also found to be induced following ischemia/reperfusion injury .…”

Section: Discussionmentioning

confidence: 99%

Cardiac Intravoxel Incoherent Motion Diffusion‐Weighted Magnetic Resonance Imaging With T1 Mapping to Assess Myocardial Perfusion and Fibrosis in Systemic Sclerosis: Association With Cardiac Events From a Prospective Cohort Study

Terrier

Dechartres

Gouya

et al. 2020

Arthritis & Rheumatology

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Objective Myocardial involvement may occur during systemic sclerosis (SSc) and can lead to impaired myocardial contraction and/or arrhythmia. Cardiac magnetic resonance imaging (MRI) is used for noninvasive characterization of the myocardium. The aim of this study was to evaluate the utility of cardiac MRI with intravoxel incoherent motion (IVIM) diffusion‐weighted imaging (DWI) and longitudinal relaxation time (T1) sequence mapping for assessment of myocardial microvascular and interstitium impairment in SSc. Methods In this single‐center prospective cohort study, 40 consecutive patients with SSc and 20 healthy controls were assessed by cardiac MRI with IVIM DWI and T1 mapping sequences on a 3T scanning system. Images were analyzed independently by 2 assessors, and Bland‐Altman plots were used to assess interreader concordance and reproducibility. Characteristics of the patients were compared according to quartiles of T1 and perfusion fraction (f‐coefficient) values, using exact Cochran‐Ermitage trend tests for qualitative variables and analysis of variance for quantitative variables. Kaplan‐Meier cardiac events–free survival curves were plotted and compared with a log‐rank test for trend. Results T1 values were higher in SSc patients than in healthy controls, and were higher in the diffuse cutaneous SSc (dcSSc) subset (P = 0.02). Higher T1 values were associated with the immunologic pattern seen in patients with the dcSSc form (P = 0.0001), a higher modified Rodnan skin thickness score (MRSS) (P = 0.003), and a higher frequency of interstitial lung disease (P = 0.03). Moreover, higher T1 values were correlated with higher MRSS scores (r = +0.32, P = 0.04) and reduced forced vital capacity (r = −0.34, P = 0.048), and tended to be correlated with reduced total lung capacity (r = −0.30, P = 0.07). Lower f‐coefficient values, as a measure of decreased tissue perfusion, were associated with less frequent use of vasodilators (P = 0.02 for angiotensin‐converting enzyme inhibitors and P = 0.06 for calcium‐channel blockers) and more frequent use of glucocorticoids (P = 0.02). The f‐coefficients were inversely correlated with the T1 values (r = −0.31, P = 0.02). Furthermore, higher T1 values were associated with higher incidence of cardiac events (log‐rank test for trend P = 0.03). Conclusion Increased T1 values, potentially suggesting microscopic fibrosis, were observed more frequently in patients with dcSSc, and higher T1 values were associated with interstitial lung disease and more frequent cardiac events during follow‐up. The results of this study show that cardiac MRI with T1 mapping sequences and IVIM DWI may be useful in assessing myocardial involvement in patients with SSc.

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“…Autoimmune-prone MRL mouse strains and their parent strain LgJ have been promoted as a mammalian regeneration model (Clark et al, 1998). Paradoxically, while these strains possess enhanced rates of healing, published reports across most injury models have demonstrated that they do not regenerate (Colwell et al, 2006; Gawriluk et al, 2016; Moseley et al, 2011; Smiley et al, 2014). Studies have documented that the healing response of the MRL mouse differs depending upon the type of injury, be it the ear pinna or other tissues (Beare et al, 2006; Colwell et al, 2006; Davis et al, 2007; Kench et al, 1999; Rajnoch et al, 2003; Tolba et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Macrophages are necessary for epimorphic regeneration in African spiny mice

Simkin

Gawriluk

Gensel

et al. 2017

eLife

164

162

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How the immune system affects tissue regeneration is not well understood. In this study, we used an emerging mammalian model of epimorphic regeneration, the African spiny mouse, to examine cell-based inflammation and tested the hypothesis that macrophages are necessary for regeneration. By directly comparing inflammatory cell activation in a 4 mm ear injury during regeneration (Acomys cahirinus) and scarring (Mus musculus), we found that both species exhibited an acute inflammatory response, with scarring characterized by stronger myeloperoxidase activity. In contrast, ROS production was stronger and more persistent during regeneration. By depleting macrophages during injury, we demonstrate a functional requirement for these cells to stimulate regeneration. Importantly, the spatial distribution of activated macrophage subtypes was unique during regeneration with pro-inflammatory macrophages failing to infiltrate the regeneration blastema. Together, our results demonstrate an essential role for inflammatory cells to regulate a regenerative response.DOI: http://dx.doi.org/10.7554/eLife.24623.001

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Increased fibrosis and progression to heart failure in MRL mice following ischemia/reperfusion injury

Cited by 22 publications

References 32 publications

Novel Model of Tendon Regeneration Reveals Distinct Cell Mechanisms Underlying Regenerative and Fibrotic Tendon Healing

Novel Model of Tendon Regeneration Reveals Distinct Cell Mechanisms Underlying Regenerative and Fibrotic Tendon Healing

Cardiac Intravoxel Incoherent Motion Diffusion‐Weighted Magnetic Resonance Imaging With T1 Mapping to Assess Myocardial Perfusion and Fibrosis in Systemic Sclerosis: Association With Cardiac Events From a Prospective Cohort Study

Macrophages are necessary for epimorphic regeneration in African spiny mice

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