Amy Cantilena

Erythropoietin modulation is associated with improved homing and engraftment after umbilical cord blood transplantation

Umbilical cord blood (UCB) engraftment is in part limited by graft cell dose, generally one log less than that of bone marrow (BM)/peripheral blood (PB) cell grafts. Strategies toward increasing hematopoietic stem/progenitor cell (HSPC) homing to BM have been assessed to improve UCB engraftment. Despite recent progress, a complete understanding of how HSPC homing and engraftment are regulated is still elusive. We provide evidence that blocking erythropoietin (EPO)-EPO receptor (R) signaling promotes homing to BM and early engraftment of UCB CD34+ cells. A significant population of UCB CD34+ HSPC expresses cell surface EPOR. Exposure of UCB CD34+ HSPC to EPO inhibits their migration and enhances erythroid differentiation. This migratory inhibitory effect was reversed by depleting EPOR expression on HSPC. Moreover, systemic reduction in EPO levels by hyperbaric oxygen (HBO) used in a preclinical mouse model and in a pilot clinical trial promoted homing of transplanted UCB CD34+ HSPC to BM. Such a systemic reduction of EPO in the host enhanced myeloid differentiation and improved BM homing of UCB CD34+ cells, an effect that was overcome with exogenous EPO administration. Of clinical relevance, HBO therapy before human UCB transplantation was well-tolerated and resulted in transient reduction in EPO with encouraging engraftment rates and kinetics. Our studies indicate that systemic reduction of EPO levels in the host or blocking EPO-EPOR signaling may be an effective strategy to improve BM homing and engraftment after allogeneic UCB transplantation. This clinical trial was registered at www.ClinicalTrials.gov (#NCT02099266).

ADULT BONE MARROW CELL THERAPY IN PATIENTS WITH ACUTE MYOCARDIAL INFARCTION: A META-ANALYSIS OF RANDOMIZED CONTROLLED TRIALS USING CARDIAC MAGNETIC RESONANCE IMAGING

Randomized controlled trials (RCTs) evaluating the efficacy of bone marrow cells (BMCs) in patients with acute myocardial infarction (AMI) have yielded discordant results. These discrepant results may potentially be attributed to use of different cardiac imaging techniques. Most studies have

STAT3 balances myocyte hypertrophy vis-à-vis autophagy in response to Angiotensin II by modulating the AMPKα/mTOR axis

Signal transducers and activators of transcription 3 (STAT3) is known to participate in various cardiovascular signal transduction pathways, including those responsible for cardiac hypertrophy and cytoprotection. However, the role of STAT3 signaling in cardiomyocyte autophagy remains unclear. We tested the hypothesis that Angiotensin II (Ang II)-induced cardiomyocyte hypertrophy is effected, at least in part, through STAT3-mediated inhibition of cellular autophagy. In H9c2 cells, Ang II treatment resulted in STAT3 activation and cellular hypertrophy in a dose-dependent manner. Ang II enhanced autophagy, albeit without impacting AMPKα/mTOR signaling or cellular ADP/ATP ratio. Pharmacologic inhibition of STAT3 with WP1066 suppressed Ang II-induced myocyte hypertrophy and mRNA expression of hypertrophy-related genes ANP and β-MHC. These molecular events were recapitulated in cells with STAT3 knockdown. Genetic or pharmacologic inhibition of STAT3 significantly increased myocyte ADP/ATP ratio and enhanced autophagy through AMPKα/mTOR signaling. Pharmacologic activation and inhibition of AMPKα attenuated and exaggerated, respectively, the effects of Ang II on ANP and β-MHC gene expression, while concomitant inhibition of STAT3 accentuated the inhibition of hypertrophy. Together, these data indicate that novel nongenomic effects of STAT3 influence myocyte energy status and modulate AMPKα/mTOR signaling and autophagy to balance the transcriptional hypertrophic response to Ang II stimulation. These findings may have significant relevance for various cardiovascular pathological processes mediated by Ang II signaling.

NF-KB INHIBITION PROTECTS AGAINST MYOCARDIAL ISCHEMIA/REPERFUSION INJURY VIA ACTIVATION OF ANTIAPOPTOTIC SIGNALING

The molecular details of nuclear factor-kappaB (NF-kB) signaling during myocardial ischemia/reperfusion (I/R) injury remain poorly understood. We hypothesized that inhibition of NF-kB would prevent cell death. We used transgenic mice overexpressing a mutant IkBα with consequent cardiac-specific

WNT11 PRETREATMENT PROTECTS AGAINST OXIDATIVE STRESS-INDUCED APOPTOSIS BY STAT3 ACTIVATION

Noncanonical Wnt11 signaling plays a key role in heart development. Very little is known about Wnt11 signaling in cardiomyocyte survival. We hypothesized that exposure to Wnt11 will induce a cytoprotective program and promote cardiomyocyte survival against oxidative stress. The effects of Wnt11 on