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The ability of extracellular vesicles (EVs) to regulate a broad range of cellular processes has recently been exploited for the treatment of diseases. For example, EVs secreted by therapeutic cells injected into infarcted hearts can induce recovery through the delivery of cell-specific microRNAs. However, retention of the EVs and the therapeutic effects are short-lived. Here, we show that an engineered hydrogel patch capable of slowly releasing EVs secreted from cardiomyocytes (CMs) derived from induced pluripotent stem cells reduced arrhythmic burden, promoted ejection-fraction recovery, decreased CM apoptosis 24 h after infarction, and reduced infarct size and cell hypertrophy 4 weeks post-infarction when implanted onto infarcted rat hearts. We also show that EVs are enriched with cardiac-specific microRNAs known to modulate CM-specific processes. The extended delivery of EVs secreted from induced-pluripotent-stem-cell-derived CMs into the heart may help us to treat heart injury and to understand heart recovery. A hydrogel patch for the sustained delivery of extracellular vesicles from cardiomyocytes derived from induced pluripotent stem cells improves tissue regeneration in infarcted rat hearts.

The number of available donor organs limits lung transplantation, the only lifesaving therapy for the increasing population of patients with end-stage lung disease. A prevalent etiology of injury that renders lungs unacceptable for transplantation is gastric aspiration, a deleterious insult to the pulmonary epithelium. Currently, severely damaged donor lungs cannot be salvaged with existing devices or methods. Here we report the regeneration of severely damaged lungs repaired to meet transplantation criteria by utilizing an interventional cross-circulation platform in a clinically relevant swine model of gastric aspiration injury. Enabled by cross-circulation with a living swine, prolonged extracorporeal support of damaged lungs results in significant improvements in lung function, cellular regeneration, and the development of diagnostic tools for non-invasive organ evaluation and repair. We therefore propose that the use of an interventional cross-circulation platform could enable recovery of otherwise unsalvageable lungs and thus expand the donor organ pool. Gastric aspiration severely injures donor lungs, frequently making them unacceptable for transplantation. Here the authors show that an interventional cross-circulation platform enables the regeneration of severely damaged lungs in a swine model of gastric aspiration injury.

Regeneration of normal shape, architecture, and function of craniofacial tissues following congenital abnormality, trauma, or surgical treatment presents special problems to tissue engineering. Because of the great variations in properties of these tissues, currently available treatment options fall short of adequate care. We propose that the engineering of personalized bone graft customized to the patient and the specific clinical condition would revolutionize the way we currently treat craniofacial defects and discuss some of the current and emerging treatment modalities.

Galactic cosmic radiation (GCR) is one of the most serious risks posed to astronauts during missions to the Moon and Mars. Experimental models capable of recapitulating human physiology are critical to understanding the effects of radiation on human organs and developing radioprotective measures against space travel exposures. The effects of systemic radiation are studied using a multi‐organ‐on‐a‐chip (multi‐OoC) platform containing engineered tissue models of human bone marrow (site of hematopoiesis and acute radiation damage), cardiac muscle (site of chronic radiation damage) and liver (site of metabolism), linked by vascular circulation with an endothelial barrier separating individual tissue chambers from the vascular perfusate. Following protracted neutron radiation, the most damaging radiation component in deep space, a greater deviation of tissue function is observed as compared to the same cumulative dose delivered acutely. Further, by characterizing engineered bone marrow (eBM)‐derived immune cells in circulation, 58 unique genes specific to the effects of protracted neutron dosing are identified, as compared to acutely irradiated and healthy tissues. It propose that this bioengineered platform allows studies of human responses to extended radiation exposure in an “astronaut‐on‐a‐chip” model that can inform measures for mitigating cosmic radiation injury. In this work, the effects of galactic cosmic radiation are studied using a human multi‐organ‐on‐chip platform consisting of bone marrow (acute radiation damage), heart muscle (chronic radiation damage), and liver (metabolism). The tissues are matured in culture, linked by vascular circulation, and exposed to simulated cosmic radiation to assess their molecular, structural, and functional effects on human organs.

Cardiac tissues generated from human induced pluripotent stem cells (iPSCs) can serve as platforms for patient-specific studies of physiology and disease 1 – 6 . However, the predictive power of these models is presently limited by the immature state of the cells 1 , 2 , 5 , 6 . Here we show that this fundamental limitation can be overcome if cardiac tissues are formed from early-stage iPSC-derived cardiomyocytes soon after the initiation of spontaneous contractions and are subjected to physical conditioning with increasing intensity over time. After only four weeks of culture, for all iPSC lines studied, such tissues displayed adult-like gene expression profiles, remarkably organized ultrastructure, physiological sarcomere length (2.2 µm) and density of mitochondria (30%), the presence of transverse tubules, oxidative metabolism, a positive force–frequency relationship and functional calcium handling. Electromechanical properties developed more slowly and did not achieve the stage of maturity seen in adult human myocardium. Tissue maturity was necessary for achieving physiological responses to isoproterenol and recapitulating pathological hypertrophy, supporting the utility of this tissue model for studies of cardiac development and disease. A tissue culture system that provides an increasing intensity of electromechanical stimulation over time enables an in vitro model of cardiac tissue derived from human induced pluripotent stem cells to develop many of the characteristics of adult cardiac tissue.

Hematopoietic stem cells (HSCs) regenerate after myeloablation, a procedure that adversely disrupts the bone marrow and drives leptin receptor-expressing cells, a key niche component, to differentiate extensively into adipocytes. Regeneration of the bone marrow niche is associated with the resolution of adipocytes, but the mechanisms remain poorly understood. Using Plin1-creER knock-in mice, we followed the fate of adipocytes in the regenerating niche in vivo. We found that bone marrow adipocytes were highly dynamic and dedifferentiated to leptin receptor-expressing cells during regeneration after myeloablation. Bone marrow adipocytes could give rise to osteolineage cells after skeletal injury. The cellular fate of steady-state bone marrow adipocytes was also plastic. Deletion of adipose triglyceride lipase ( Atgl ) from bone marrow stromal cells, including adipocytes, obstructed adipocyte dedifferentiation and led to severely compromised regeneration of HSCs as well as impaired B lymphopoiesis after myeloablation, but not in the steady state. Thus, the regeneration of HSCs and their niche depends on the cellular plasticity of bone marrow adipocytes. Mouse lineage tracing in regenerating bone marrow after myeloablation shows a dynamic dedifferentiation of mature adipocytes into bone marrow stromal cells. Lipolysis disruption obstructs adipocyte dedifferentiation and hematopoietic stem cell regeneration.

For a long time, cartilage has been a major focus of the whole field of tissue engineering, both because of the constantly growing need for more effective options for joint repair and the expectation that this apparently simple tissue will be easy to engineer. After several decades, cartilage regeneration has proven to be anything but easy. With gratifying progress in our understanding of the factors governing cartilage development and function, and cell therapy being successfully used for several decades, there is still a lot to do. We lack reliable methods to generate durable articular cartilage that would resemble the original tissue lost to injury or disease. The question posed here is whether the answer would come from the methods using cells, biomaterials, or tissue engineering. We present a concise review of some of the most meritorious efforts in each area, and propose that the solution will most likely emerge from the ongoing attempts to recapitulate certain aspects of native cartilage development. While an ideal recipe for cartilage regeneration is yet to be formulated, we believe that it will contain cell, biomaterial, and tissue engineering approaches, blended into an effective method for seamless repair of articular cartilage.

We summarize research approaches and findings on bone healing and regeneration that were presented at a workshop at the 60th annual meeting of the Orthopedic Research Society (ORS) in New Orleans in 2014. The workshop was designed to discuss the role of inflammation in bone regeneration in the context of fundamental biology, and to develop therapeutic strategies that involve immune modulation. Delayed or non-healing of bone is a major clinical problem, with around 10% of fracture patients suffering from unsatisfying healing outcomes. Inflammation is traditionally seen as a defense mechanism, but was recently found essential in supporting and modulating regenerative cascades. In bone healing, macrophages and T- and B-cells interact with progenitor cells, bone forming osteoblasts and remodeling osteoclasts. Among the cells of the innate immunity, macrophages are promising candidates for targets in immune-modulatory interventions that would overcome complications in bone healing and bone-related diseases. Among the cells of the adaptive immune system, CD8+ T cells have been shown to have a negative impact on bone fracture healing outcome, whereas regulatory T cells could be promising candidates that have a positive, modulating effect on bone fracture healing. This workshop addressed recent advances and key challenges in this exciting interdisciplinary research field.

Pathogenic mutations in Bcl2-associated athanogene 3 (BAG3) cause genetic dilated cardiomyopathy (DCM), a disease characterized by ventricular dilation, systolic dysfunction, and fibrosis. Previous studies have demonstrated that BAG3 mediates sarcomeric protein turnover through chaperone-assisted selective autophagy to maintain sarcomere integrity in the human heart. Although mouse models provide valuable insights into whole-organism effects of BAG3 knockout or pathogenic variants, their utility is limited by species-specific differences in pathophysiology, which often do not translate to humans and contribute to the failure of clinical trials. As a result, the development of induced pluripotent stem cell-derived cardiomyocytes (iCM) and engineered heart tissues presents a promising alternative for studying adult-onset cardiac diseases. Here, we used genome engineering to generate an isogenic pseudo-wild-type control cell line from a patient-derived iPSC line carrying a pathogenic BAG3 variant, clinically presenting with DCM. While monolayer iCMs recapitulated some features of BAG3-mediated DCM, such as reduced autophagy, mitochondrial membrane potential, and decreased HSPB8 stability, they failed to develop the age-associated impairment in sarcomere integrity. Therefore, we developed a mature, patient-specific, human engineered heart tissue model of BAG3-mediated DCM and compared it to its isogenic healthy control. We demonstrated successful recapitulation of adult-like features of the clinically observed disorganized sarcomeres and impaired tissue contractility, thereby providing a platform to investigate BAG3-related pathophysiology and therapeutic interventions. Graphical abstract

In a developing organism, tissues emerge from coordinated sequences of cell renewal, differentiation, and assembly that are orchestrated by spatial and temporal gradients of multiple regulatory factors. The composition, architecture, signaling, and biomechanics of the cellular microenvironment act in concert to provide the necessary cues regulating cell function in the developing and adult organism. With recent major advances in stem cell biology, tissue engineering is becoming increasingly oriented toward biologically inspired in vitro cellular microenvironments designed to guide stem cell growth, differentiation, and functional assembly. The premise is that to unlock the full potential of stem cells, at least some aspects of the dynamic three-dimensional (3D) environments that are associated with their renewal, differentiation, and assembly in native tissues need to be reconstructed. In the general context of tissue engineering, we discuss the environments for guiding stem cell function by an interactive use of biomaterial scaffolds and bioreactors, and focus on the interplay between molecular and physical regulatory factors. We highlight some illustrative examples of controllable cell environments developed through the interaction of stem cell biology and tissue engineering at multiple levels.