TBX3 is dynamically expressed in pancreatic organogenesis and fine-tunes regeneration.

BACKGROUND: The reactivation of genetic programs from early development is a common mechanism for injury-induced organ regeneration. T-box 3 (TBX3) is a member of the T-box family of transcription factors previously shown to regulate pluripotency and subsequent lineage commitment in a number of tissues, including limb and lung. TBX3 is also involved in lung and heart organogenesis. Here, we provide a comprehensive and thorough characterization of TBX3 and its role during pancreatic organogenesis and regeneration. RESULTS: We interrogated the level and cell specificity of TBX3 in the developing and adult pancreas at mRNA and protein levels at multiple developmental stages in mouse and human pancreas. We employed conditional mutagenesis to determine its role in murine pancreatic development and in regeneration after the induction of acute pancreatitis. We found that Tbx3 is dynamically expressed in the pancreatic mesenchyme and epithelium. While Tbx3 is expressed in the developing pancreas, its absence is likely compensated by other factors after ablation from either the mesenchymal or epithelial compartments. In an adult model of acute pancreatitis, we found that a lack of Tbx3 resulted in increased proliferation and fibrosis as well as an enhanced inflammatory gene programs, indicating that Tbx3 has a role in tissue homeostasis and regeneration. CONCLUSIONS: TBX3 demonstrates dynamic expression patterns in the pancreas. Although TBX3 is dispensable for proper pancreatic development, its absence leads to altered organ regeneration after induction of acute pancreatitis.

Functional Genomic Screening During Somatic Cell Reprogramming Identifies DKK3 as a Roadblock of Organ Regeneration.

Somatic cell reprogramming and tissue repair share relevant factors and molecular programs. Here, Dickkopf-3 (DKK3) is identified as novel factor for organ regeneration using combined transcription-factor-induced reprogramming and RNA-interference techniques. Loss of Dkk3 enhances the generation of induced pluripotent stem cells but does not affect de novo derivation of embryonic stem cells, three-germ-layer differentiation or colony formation capacity of liver and pancreatic organoids. However, DKK3 expression levels in wildtype animals and serum levels in human patients are elevated upon injury. Accordingly, Dkk3-null mice display less liver damage upon acute and chronic failure mediated by increased proliferation in hepatocytes and LGR5+ liver progenitor cell population, respectively. Similarly, recovery from experimental pancreatitis is accelerated. Regeneration onset occurs in the acinar compartment accompanied by virtually abolished canonical-Wnt-signaling in Dkk3-null animals. This results in reduced expression of the Hedgehog repressor Gli3 and increased Hedgehog-signaling activity upon Dkk3 loss. Collectively, these data reveal Dkk3 as a key regulator of organ regeneration via a direct, previously unacknowledged link between DKK3, canonical-Wnt-, and Hedgehog-signaling.

Myocardial protection in cardiac surgery: Del Nido versus blood cardioplegia.

Objectives: del Nido cardioplegia which was traditionally used for myocardial protection in pediatric congenital heart surgery is now being extensively utilized in adult cardiac surgery. The aim of this study was to compare the safety and efficacy of del Nido cardioplegia (DNC) with blood cardioplegia (BC). Materials and Methods: This is a historical cohort study using secondary data. Two hundred and eighty six patients who underwent coronary artery bypass graft (CABG) or valve surgery were included. They were divided into 2 matched cohorts of which 143 patients received BC and 143 patients received DNC. Results: There was no difference in cardiopulmonary bypass time (P = 0.516) and clamp time (P = 0.650) between the groups. The redosing of cardioplegia was significantly less for DNC (1.13 vs. 2.35, P = <0.001). The post bypass hemoglobin was higher for DNC (9.1 vs. 8.7, P = 0.011). The intraoperative and postoperative blood transfusion was comparable (P = 0.344) (P = 0.40). The incidence of clamp release ventricular fibrillation (P = 0.207) was similar. The creatine kinase-MB isotype levels for the CABG patients were comparable on all 3 days (P = 0.104), (P = 0.106), and (P = 0.158). The postoperative left ventricle ejection fraction was lesser but within normal range in the DNC group (53.4 vs. 56.0, P = <0.001). The duration of ventilation (P = 0.186), ICU days (P = 0.931), and postoperative complications (P = 0.354) were comparable. There was no 30-day mortality or postoperative myocardial infarction in both the groups. Conclusion: DNC provides equivalent myocardial protection, efficacy, and surgical workflow and had comparable clinical outcomes to that of BC. This study shows that DNC is a safe alternate to BC in CABG and valve surgeries.