CTGF-D4 Amplifies LRP6 Signaling to Promote Grafts of Adult Epicardial-derived Cells That Improve Cardiac Function After Myocardial Infarction.

Transplantation of stem/progenitor cells holds promise for cardiac regeneration in patients with myocardial infarction (MI). Currently, however, low cell survival and engraftment after transplantation present a major barrier to many forms of cell therapy. One issue is that ligands, receptors, and signaling pathways that promote graft success remain poorly understood. Here, we prospectively isolate uncommitted epicardial cells from the adult heart surface by CD104 (ß-4 integrin) and demonstrate that C-terminal peptide from connective tissue growth factor (CTGF-D4), when combined with insulin, effectively primes epicardial-derived cells (EPDC) for cardiac engraftment after MI. Similar to native epicardial derivatives that arise from epicardial EMT at the heart surface, the grafted cells migrated into injured myocardial tissue in a rat model of MI with reperfusion. By echocardiography, at 1 month after MI, we observed significant improvement in cardiac function for animals that received epicardial cells primed with CTGF-D4/insulin compared with those that received vehicle-primed (control) cells. In the presence of insulin, CTGF-D4 treatment significantly increased the phosphorylation of Wnt co-receptor LRP6 on EPDC. Competitive engraftment assays and neutralizing/blocking studies showed that LRP6 was required for EPDC engraftment after transplantation. Our results identify LRP6 as a key target for increasing EPDC engraftment after MI and suggest amplification of LRP6 signaling with CTGF-D4/insulin, or by other means, may provide an effective approach for achieving successful cellular grafts in regenerative medicine.

Prevalence and outcomes of hypertension in pregnancy in non-metropolitan and metropolitan communities.

OBJECTIVES: Hypertension during pregnancy is a leading cause of birthing parent mortality and adverse pregnancy outcomes. Since non-metropolitan communities face higher rates of several risk factors for hypertension in pregnancy and shortages in obstetrical services, persons residing in non-metropolitan areas may be at increased risk for adverse events compared to those living in metropolitan areas. Our study objectives were to examine by non-metropolitan vs. metropolitan birthing parent residence (1) the prevalence of chronic hypertension (cHTN) and hypertensive disorders of pregnancy (HDP), and (2) the prevalence of cesarean delivery, preterm birth, low birth weight, APGAR <7 at 5 min, NICU admission, and stillbirth/neonatal death among the group of birthing parents with cHTN and among the group of birthing parents with HDP. METHODS: Using U.S. Natality data from 2016 to 2018, we described the prevalence of cHTN and HDP and the association of each with several birthing parent and neonatal outcomes, stratified by non-metropolitan versus metropolitan county of birthing parent residence. Multivariable Poisson regression models were used to calculate adjusted prevalence ratios for these adverse outcomes. RESULTS: The prevalence of cHTN among pregnant individuals was 2.2% in non-metropolitan areas and 1.8% in metropolitan areas. For HDP, the prevalence was 7.4% in non-metropolitan areas and 6.6% in metropolitan areas. After adjusting for several sociodemographic characteristics among those with HDP, the prevalence ratio for an APGAR score < 7 at 5 min (aPR 1.34, 95% CI 1.29-1.38) and stillbirth/neonatal death (aPR 1.36, 95% CI 1.15-1.62) was increased among offspring born to birthing parents who resided in non-metropolitan counties. Similar results were seen among those with cHTN. CONCLUSIONS: The prevalence of cHTN and HDP is elevated among birthing parents residing in non-metropolitan areas. Also, the prevalence of APGAR <7 and stillbirth//neonatal death following pregnancies complicated by hypertension were higher among neonates born to birthing parents residing in non-metropolitan areas. Further research should investigate the robustness of these findings using alternate definitions of rural and urban areas and the possible link between low APGAR score, low NICU admission, and stillbirth/neonatal death among birthing parents residing in non-metropolitan counties.