A small-molecule cocktail promotes mammalian cardiomyocyte proliferation and heart regeneration.

Zebrafish and mammalian neonates possess robust cardiac regeneration via the induction of endogenous cardiomyocyte (CM) proliferation, but adult mammalian hearts have very limited regenerative potential. Developing small molecules for inducing adult mammalian heart regeneration has had limited success. We report a chemical cocktail of five small molecules (5SM) that promote adult CM proliferation and heart regeneration. A high-content chemical screen, along with an algorithm-aided prediction of small-molecule interactions, identified 5SM that efficiently induced CM cell cycle re-entry and cytokinesis. Intraperitoneal delivery of 5SM reversed the loss of heart function, induced CM proliferation, and decreased cardiac fibrosis after rat myocardial infarction. Mechanistically, 5SM potentially targets α1 adrenergic receptor, JAK1, DYRKs, PTEN, and MCT1 and is connected to lactate-LacRS2 signaling, leading to CM metabolic switching toward glycolysis/biosynthesis and CM de-differentiation before entering the cell-cycle. Our work sheds lights on the understanding CM regenerative mechanisms and opens therapeutic avenues for repairing the heart.

Evaluation of the permissible maximum angle of the tibial tunnel in transtibial anatomic posterior cruciate ligament reconstruction by computed tomography.

INTRODUCTION: Excessive angle of the tibial tunnel may cause breakage of the posterior cortex in transtibial anatomic posterior cruciate ligament (PCL) reconstruction. However, a few studies have determined the permissible maximum angle of the tibial tunnel. The purpose of this study was to determine the permissible maximum angle of the tibial tunnel relative to the tibial plateau in transtibial anatomic PCL reconstruction and characterize the anatomic parameters of the tibial PCL attachment position. MATERIALS AND METHODS: Computed tomography (CT) scans of a consecutive series of 408 adult knees with normal PCL attachment were measured. The parameters measured were the permissible maximum angle (PMA) of the 10 mm-diameter tibial tunnel relative to the tibial plateau, the distance from the anterior orifice of the tibial tunnel to the tibial tuberosity (OTD), the anterior-posterior diameter (APD) of the tibial plateau, the distance from the center of PCL attachment site to the posterior edge of the tibial plateau (PPED), and the angle between the tibial plateau and the posterior tibial slope where the PCL insertion site was (PSA). Subgroup analysis was performed to determine the correlations between parameters, and sex, age, and height. The measurement reliability was evaluated by intraclass correlation coefficients (ICCs). RESULTS: The average value of PMA was 48.2 ± 5.4°, and it was not affected by sex, age, and height (P > 0.05). The values of OTD, APD, PPED, PSA, and height were significantly higher in males than females (OTD, P < 0.01; APD, P < 0.01; PPED, P < 0.01; PSA, P = 0.019; height, P < 0.01). With regard to age, we stratified the cases into three groups: the young (18-30 years old), the middle-aged (31-45 years old), and the elderly (46-60 years old). The mean value of OTD, APD, and height were significantly lower in the elderly than that in the middle-aged (P < 0.01, P < 0.01, P < 0.01, respectively). With regard to height, we stratified the cases into three groups: ~ 1.65 m (1), 1.66 ~ 1.75 m (2), and 1.76 m ~ (3). The mean value of OTD, APD, and PPED significantly increased with height, P < 0.05. The mean value of PSA was significant higher in II group than that in I group (P = 0.034). CONCLUSIONS: There should be a limit to the angle of the tibial tunnel in transtibial anatomic PCL reconstruction to prevent the fracture of posterior tunnel wall. The permissible maximum angle (PMA) of the 10 mm-diameter tibial tunnel relative to the tibial plateau was 48.2°. Besides, the determination of the value of OTD, APD, PPED, and PSA could provide a clinical reference to insertion site, depth, and angle of the tibial drill guide in PCL reconstruction.