Biodegradable scaffolds seeded with bone marrow mononuclear cells (BMCs) are the earliest tissue-engineered vascular grafts (TEVGs) to be used clinically. These TEVGs transform into living blood vessels in vivo, with an endothelial cell (EC) lining invested by smooth muscle cells (SMCs); however, the process by which this occurs is unclear. To test if the seeded BMCs differentiate into the mature vascular cells of the neovessel, we implanted an immunodeficient mouse recipient with human BMC (hBMC)-seeded scaffolds. As in humans, TEVGs implanted in a mouse host as venous interposition grafts gradually transformed into living blood vessels over a 6-month time course. Seeded hBMCs, however, were no longer detectable within a few days of implantation. Instead, scaffolds were initially repopulated by mouse monocytes and subsequently repopulated by mouse SMCs and ECs. Seeded BMCs secreted significant amounts of monocyte chemoattractant protein-1 and increased early monocyte recruitment. These findings suggest TEVGs transform into functional neovessels via an inflammatory process of vascular remodeling.bone marrow | monocyte chemoattractant protein-1 | tissue engineering | neovascularization C ongenital heart disease is a leading cause of infant mortality, often requiring early surgical intervention to correct fatal cardiovascular malformations. Prosthetic vascular grafts are widely used in these reconstructive operations, but revisions are often necessary because of their inability to grow or effectively remodel within a growing child (1-3). A strategy to address this issue is the use of living tissue-engineered vascular grafts (TEVGs). Constructed from biodegradable polyester tubes seeded with autologous bone marrow mononuclear cells (BMCs), these grafts undergo extensive remodeling in animal recipients and appear to transform into living blood vessels, similar in morphology and function to the native veins into which they are interposed (4, 5). Ongoing clinical studies evaluating BMC-seeded grafts as venous conduits for congenital heart surgery report excellent safety profiles and 100% patency rates at 1-3 years of follow-up (6-8). Additionally, these grafts demonstrate growth potential, suggesting they may be more effective for the pediatric patient population than currently available vascular grafts (8,9).Although the functional efficacy and clinical utility of TEVGs are promising, little is known about how these BMC-seeded polyester tubes transform into living blood vessels in host recipients. It has been proposed that stem cells within the seeded BMC population differentiate into the endothelial cells (ECs) and smooth muscle cells (SMCs) of the developing neovessel, ultimately replacing the degrading polyester tube (10). This hypothesis, however, has not been directly examined.We recently developed a method for constructing small-diameter biodegradable synthetic scaffolds suitable for use as vascular grafts in mice (11). These tubular scaffolds are composed of the same materials and design used in clinical TEVGs...

Interferon regulatory factor 3 (IRF3) and type I interferons (IFNs) protect against infections and cancer, but excessive IRF3 activation and type I IFN production cause autoinflammatory conditions such as Aicardi-Goutières syndrome and STING-associated vasculopathy of infancy (SAVI). Myocardial infarction (MI) elicits inflammation, but the dominant molecular drivers of MI-associated inflammation remain unclear. Here we show that ischemic cell death and uptake of cell debris by macrophages in the heart fuel a fatal response to MI by activating IRF3 and type I IFN production. In mice, single-cell RNA-seq analysis of 4,215 leukocytes isolated from infarcted and non-infarcted hearts showed that MI provokes activation of an IRF3-interferon axis in a distinct population of interferon-inducible cells (IFNICs) that were classified as cardiac macrophages. Mice genetically deficient in cyclic GMP-AMP synthase (cGAS), its adaptor STING, IRF3, or the type I IFN receptor IFNAR exhibited impaired interferon-stimulated gene (ISG) expression and, in the case of mice deficient in IRF3 or IFNAR, improved survival after MI as compared to controls. Interruption of IRF3-dependent signaling resulted in decreased cardiac expression of inflammatory cytokines and chemokines and decreased inflammatory cell infiltration of the heart, as well as in attenuated ventricular dilation and improved cardiac function. Similarly, treatment of mice with an IFNAR-neutralizing antibody after MI ablated the interferon response and improved left ventricular dysfunction and survival. These results identify IRF3 and the type I IFN response as a potential therapeutic target for post-MI cardioprotection.

Hulsmans et al. show that cardiac macrophages expand in left ventricular diastolic dysfunction, a hallmark of heart failure with preserved ejection fraction (HFpEF) and cardiac aging. In HFpEF, macrophages shift toward a profibrotic subset that promotes ventricular stiffness.