Healthy longevity-associated protein improves cardiac function in murine models of cardiomyopathy with preserved ejection fraction.

Aims: Aging is influenced by genetic determinants and comorbidities, among which diabetes increases the risk for heart failure with preserved ejection fraction. There is no therapy to prevent heart dysfunction in aging and diabetic individuals. In previous studies, a single administration of the longevity-associated variant (LAV) of the human BPIFB4 gene halted heart decline in older and type 2 diabetic mice.

The tyrosine kinase inhibitor Dasatinib reduces cardiac steatosis and fibrosis in obese, type 2 diabetic mice.

Background: Cardiac steatosis is an early yet overlooked feature of diabetic cardiomyopathy. There is no available therapy to treat this condition. Tyrosine kinase inhibitors (TKIs) are used as first or second-line therapy in different types of cancer.

Approaches for the isolation and long-term expansion of pericytes from human and animal tissues.

Pericytes surround capillaries in every organ of the human body. They are also present around the , the small blood vessels that supply the walls of larger arteries and veins. The clinical interest in pericytes is rapidly growing, with the recognition of their crucial roles in controlling vascular function and possible therapeutic applications in regenerative medicine.

The longevity-associated BPIFB4 gene supports cardiac function and vascularization in ageing cardiomyopathy.

Aims: The ageing heart naturally incurs a progressive decline in function and perfusion that available treatments cannot halt. However, some exceptional individuals maintain good health until the very late stage of their life due to favourable gene-environment interaction. We have previously shown that carriers of a longevity-associated variant (LAV) of the BPIFB4 gene enjoy prolonged health spans and lesser cardiovascular complications.

Corrigendum: Accelerated cardiac aging in patients with congenital heart disease.

[This corrects the article DOI: 10.3389/fcvm.2022.

Accelerated Cardiac Aging in Patients With Congenital Heart Disease.

An increasing number of patients with congenital heart disease (CHD) survive into adulthood but develop long-term complications including heart failure (HF). Cellular senescence, classically defined as stable cell cycle arrest, is implicated in biological processes such as embryogenesis, wound healing, and aging. Senescent cells have a complex senescence-associated secretory phenotype (SASP), involving a range of pro-inflammatory factors with important paracrine and autocrine effects on cell and tissue biology.

Wharton's Jelly-Mesenchymal Stem Cell-Engineered Conduit for Pulmonary Artery Reconstruction in Growing Piglets.

Surgical treatment of congenital heart defects affecting the right ventricular outflow tract often requires complex reconstruction and multiple reoperations. With a randomized controlled trial, we compared a novel tissue-engineered small intestine submucosa-based graft for pulmonary artery reconstruction (seeded with mesenchymal stem cells derived from Wharton's Jelly) with conventional small intestine submucosa in growing piglets. Six months after implantation, seeded grafts showed integration with host tissues at cellular level and exhibited growth potential on transthoracic echocardiography and cardiovascular magnetic resonance.

Reconstruction of the Swine Pulmonary Artery Using a Graft Engineered With Syngeneic Cardiac Pericytes.

The neonatal heart represents an attractive source of regenerative cells. Here, we report the results of a randomized, controlled, investigator-blinded preclinical study, which assessed the safety and effectiveness of a matrix graft cellularized with cardiac pericytes (CPs) in a piglet model of pulmonary artery (PA) reconstruction. Within each of five trios formed by 4-week-old female littermate piglets, one element (the donor) was sacrificed to provide a source of CPs, while the other two elements (the graft recipients) were allowed to reach the age of 10 weeks.

Activation of Bone Marrow Adaptive Immunity in Type 2 Diabetes: Rescue by Co-stimulation Modulator Abatacept.

Chronic low-grade inflammation and alterations in innate and adaptive immunity were reported in Type 2 diabetes (T2D). Here, we investigated the abundance and activation of T cells in the bone marrow (BM) of patients with T2D. We then verified the human data in a murine model and tested if the activation of T cells can be rescued by treating mice with abatacept, an immunomodulatory drug employed for the treatment of rheumatoid arthritis.

Secreted Protein Acidic and Cysteine Rich Matricellular Protein is Enriched in the Bioactive Fraction of the Human Vascular Pericyte Secretome.

To ascertain if human pericytes produce SPARC (acronym for Secreted Protein Acidic and Cysteine Rich), a matricellular protein implicated in the regulation of cell proliferation, migration, and cell-matrix interactions; clarify if SPARC expression in cardiac pericytes is modulated by hypoxia; and determine the functional consequences of SPARC silencing. Starting from the recognition that the conditioned media (CM) of human pericytes promote proliferation and migration of cardiac stromal cells, we screened candidate mediators by mass-spectrometry analysis. Of the 14 high-confidence proteins (<1% FDR) identified in the bioactive fractions of the pericyte CM, SPARC emerged as the top-scored matricellular protein.

In Vitro and In Vivo Preclinical Testing of Pericyte-Engineered Grafts for the Correction of Congenital Heart Defects.

Background We have previously reported the possibility of using pericytes from leftovers of palliative surgery of congenital heart disease to engineer clinically certified prosthetic grafts. Methods and Results Here, we assessed the feasibility of using prosthetic conduits engineered with neonatal swine pericytes to reconstruct the pulmonary artery of 9-week-old piglets. Human and swine cardiac pericytes were similar regarding anatomical localization in the heart and antigenic profile following isolation and culture expansion.

Personalized Cardiovascular Regenerative Medicine: Targeting the Extreme Stages of Life.

Cardiovascular regenerative medicine is an exciting new approach that promises to change the current care of million people world-wide. Major emphasis was given to the quality and quantities of regenerative products, but recent evidence points to the importance of a better specification of the target population that may take advantage of these advanced medical treatments. Patient stratification is an important step in drug development.

Role of TPBG (Trophoblast Glycoprotein) Antigen in Human Pericyte Migratory and Angiogenic Activity.

Objective- To determine the role of the oncofetal protein TPBG (trophoblast glycoprotein) in normal vascular function and reparative vascularization. Approach and Results- Immunohistochemistry of human veins was used to show TPBG expression in vascular smooth muscle cells and adventitial pericyte-like cells (APCs). ELISA, Western blot, immunocytochemistry, and proximity ligation assays evidenced a hypoxia-dependent upregulation of TPBG in APCs not found in vascular smooth muscle cells or endothelial cells.

MicroRNA-532-5p Regulates Pericyte Function by Targeting the Transcription Regulator BACH1 and Angiopoietin-1.

MicroRNAs regulate endothelial function and angiogenesis, but their implication in pericyte biology remains undetermined. A PCR array, covering a panel of 379 human microRNAs, showed microRNA-532-5p to be one of the most differentially modulated by hypoxia, which was confirmed by qPCR in both skeletal muscle and adventitial pericytes. Furthermore, microRNA-532-5p was upregulated in murine muscular pericytes early after experimentally induced ischemia, decreasing below baseline after reperfusion.

Transplantation of Allogeneic Pericytes Improves Myocardial Vascularization and Reduces Interstitial Fibrosis in a Swine Model of Reperfused Acute Myocardial Infarction.

Background: Transplantation of adventitial pericytes (APCs) promotes cardiac repair in murine models of myocardial infarction. The aim of present study was to confirm the benefit of APC therapy in a large animal model.

Methods And Results: We performed a blind, randomized, placebo-controlled APC therapy trial in a swine model of reperfused myocardial infarction.

The adipokine leptin modulates adventitial pericyte functions by autocrine and paracrine signalling.

Transplantation of adventitial pericytes (APCs) improves recovery from tissue ischemia in preclinical animal models by still unknown mechanisms. This study investigates the role of the adipokine leptin (LEP) in the regulation of human APC biological functions. Transcriptomic analysis of APCs showed components of the LEP signalling pathway are modulated by hypoxia.

Perivascular cells and tissue engineering: Current applications and untapped potential.

The recent development of tissue engineering provides exciting new perspectives for the replacement of failing organs and the repair of damaged tissues. Perivascular cells, including vascular smooth muscle cells, pericytes and other tissue specific populations residing around blood vessels, have been isolated from many organs and are known to participate to the in situ repair process and angiogenesis. Their potential has been harnessed for cell therapy of numerous pathologies; however, in this Review we will discuss the potential of perivascular cells in the development of tissue engineering solutions for healthcare.

Expansion and characterization of neonatal cardiac pericytes provides a novel cellular option for tissue engineering in congenital heart disease.

Background: Living grafts produced by combining autologous heart-resident stem/progenitor cells and tissue engineering could provide a new therapeutic option for definitive correction of congenital heart disease. The aim of the study was to investigate the antigenic profile, expansion/differentiation capacity, paracrine activity, and pro-angiogenic potential of cardiac pericytes and to assess their engrafting capacity in clinically certified prosthetic grafts.

Methods And Results: CD34(pos) cells, negative for the endothelial markers CD31 and CD146, were identified by immunohistochemistry in cardiac leftovers from infants and children undergoing palliative repair of congenital cardiac defects.

Combined intramyocardial delivery of human pericytes and cardiac stem cells additively improves the healing of mouse infarcted hearts through stimulation of vascular and muscular repair.

Rationale: Optimization of cell therapy for cardiac repair may require the association of different cell populations with complementary activities.

Objective: Compare the reparative potential of saphenous vein-derived pericytes (SVPs) with that of cardiac stem cells (CSCs) in a model of myocardial infarction, and investigate whether combined cell transplantation provides further improvements.

Methods And Results: SVPs and CSCs were isolated from vein leftovers of coronary artery bypass graft surgery and discarded atrial specimens of transplanted hearts, respectively.