Heterochronic parabiosis rejuvenates the performance of old tissue stem cells at some expense to the young, but whether this is through shared circulation or shared organs is unclear. Here we show that heterochronic blood exchange between young and old mice without sharing other organs, affects tissues within a few days, and leads to different outcomes than heterochronic parabiosis. Investigating muscle, liver and brain hippocampus, in the presence or absence of muscle injury, we find that, in many cases, the inhibitory effects of old blood are more pronounced than the benefits of young, and that peripheral tissue injury compounds the negative effects. We also explore mechanistic explanations, including the role of B2M and TGF-beta. We conclude that, compared with heterochronic parabiosis, heterochronic blood exchange in small animals is less invasive and enables better-controlled studies with more immediate translation to therapies for humans.
During the Middle Ages, the partition of the cadaver of the elite members was a current practice, with highly technical treatment given to symbolic organs such as the heart. Considered mostly from a theoretical point of view, this notion of dilaceratio corporis has never been biologically explored. To assess the exact kind of embalming reserved to the heart, we performed a full biomedical analysis of the mummified heart of the English King Richard I (1199 A.D.). Here we show among other aspects, that the organ has been embalmed using substances inspired by Biblical texts and practical necessities of desiccation. We found that the heart was deposed in linen, associated with myrtle, daisy, mint, frankincense, creosote, mercury and, possibly, lime. Furthermore, the goal of using such preservation materials was to allow long-term conservation of the tissues, and good-smelling similar to the one of the Christ (comparable to the odor of sanctity).
Every element or cell in the human body produces substances that communicate and respond in an autocrine or paracrine mode, consequently affecting organs and structures that are seemingly far from each other. The same also applies to the skin. In fact, when the integrity of the skin has been altered, or when its healing process is disturbed, it becomes a source of symptoms that are not merely cutaneous. The skin is an organ, and similar to any other structure, it has different functions in addition to connections with the central and peripheral nervous system. This article examines pathological responses produced by scars, analyzing definitions and differences. At the same time, it considers the subcutaneous fascias, as this connective structure is altered when there is a discontinuous cutaneous surface. The consequence is an ample symptomatology, which is not limited to the body area where the scar is located, such as a postural or trigeminal disorder.
Organ replacement regenerative therapy is purported to enable the replacement of organs damaged by disease, injury or aging in the foreseeable future. Here we demonstrate fully functional hair organ regeneration via the intracutaneous transplantation of a bioengineered pelage and vibrissa follicle germ. The pelage and vibrissae are reconstituted with embryonic skin-derived cells and adult vibrissa stem cell region-derived cells, respectively. The bioengineered hair follicle develops the correct structures and forms proper connections with surrounding host tissues such as the epidermis, arrector pili muscle and nerve fibres. The bioengineered follicles also show restored hair cycles and piloerection through the rearrangement of follicular stem cells and their niches. This study thus reveals the potential applications of adult tissue-derived follicular stem cells as a bioengineered organ replacement therapy.
As vertebrate embryos develop to adulthood, their organs undergo marked changes in size and tissue architecture. The heart acquires muscle mass and matures structurally to fulfil increasing circulatory needs, a process that is incompletely understood. Here we used multicolour clonal analysis to define the contributions of individual cardiomyocytes as the zebrafish heart undergoes morphogenesis from a primitive embryonic structure into its complex adult form. We find that the single-cardiomyocyte-thick wall of the juvenile ventricle forms by lateral expansion of several dozen cardiomyocytes into muscle patches of variable sizes and shapes. As juvenile zebrafish mature into adults, this structure becomes fully enveloped by a new lineage of cortical muscle. Adult cortical muscle originates from a small number of cardiomyocytes–an average of approximately eight per animal–that display clonal dominance reminiscent of stem cell populations. Cortical cardiomyocytes initially emerge from internal myofibres that in rare events breach the juvenile ventricular wall, and then expand over the surface. Our results illuminate the dynamic proliferative behaviours that generate adult cardiac structure, revealing clonal dominance as a key mechanism that shapes a vertebrate organ.
The integumentary organ system is a complex system that plays important roles in waterproofing, cushioning, protecting deeper tissues, excreting waste, and thermoregulation. We developed a novel in vivo transplantation model designated as a clustering-dependent embryoid body transplantation method and generated a bioengineered three-dimensional (3D) integumentary organ system, including appendage organs such as hair follicles and sebaceous glands, from induced pluripotent stem cells. This bioengineered 3D integumentary organ system was fully functional following transplantation into nude mice and could be properly connected to surrounding host tissues, such as the epidermis, arrector pili muscles, and nerve fibers, without tumorigenesis. The bioengineered hair follicles in the 3D integumentary organ system also showed proper hair eruption and hair cycles, including the rearrangement of follicular stem cells and their niches. Potential applications of the 3D integumentary organ system include an in vitro assay system, an animal model alternative, and a bioengineered organ replacement therapy.
HIV-1 infection is enhanced by adhesive structures that form between infected and uninfected T cells called virological synapses (VSs). This mode of transmission results in the frequent co-transmission of multiple copies of HIV-1 across the VS, which can reduce sensitivity to antiretroviral drugs. Studying HIV-1 infection of humanized mice, we measured the frequency of co-transmission and the spatiotemporal organization of infected cells as indicators of cell-to-cell transmission in vivo. When inoculating mice with cells co-infected with two viral genotypes, we observed high levels of co-transmission to target cells. Additionally, micro-anatomical clustering of viral genotypes within lymphoid tissue indicates that viral spread is driven by local processes and not a diffuse viral cloud. Intravital splenic imaging reveals that anchored HIV-infected cells induce arrest of interacting, uninfected CD4(+) T cells to form Env-dependent cell-cell conjugates. These findings suggest that HIV-1 spread between immune cells can be anatomically localized into infectious clusters.
Superovulation induced by exogenous gonadotropin treatment (PMSG/hCG) increases the number of available oocytes in humans and animals. However, Superovulatory PMSG/hCG treatment is known to affect maternal environment, and these effects may result from PMSG/hCG treatment-induced oxidative stress. 2-Cys peroxiredoxins (2-Cys Prxs) act as antioxidant enzymes that protect cells from oxidative stress induced by various exogenous stimuli. Therefore, the objective of this study was to test the hypothesis that repeated PMSG/hCG treatment induces 2-Cys Prx expression and overoxidation in the reproductive tracts of female mice. Immunohistochemistry and western blotting analyses further demonstrated that, after PMSG/hCG treatment, the protein expression levels of 2-Cys Prxs increased most significantly in the ovaries, while that of Prx1 was most affected by PMSG/hCG stimulation in all tissues of the female reproductive tract. Repeated PMSG/hCG treatment eventually leads to 2-Cys Prxs overoxidation in all reproductive organs of female mice, and the abundance of the 2-Cys Prxs-SO2/3 proteins reported here supports the hypothesis that repeated superovulation induces strong oxidative stress and damage to the female reproductive tract. Our data suggest that excessive oxidative stress caused by repeated PMSG/hCG stimulation increases 2-Cys Prxs expression and overoxidation in the female reproductive organs. Intracellular 2-Cys Prx therefore plays an important role in maintaining the reproductive organ environment of female mice upon exogenous gonadotropin treatment.
Vascular calcification, occurring during late-stage vascular and valvular disease, is highly associated with chronic kidney disease-mineral and bone disorders (CKD-MBD), representing a major risk factor for cardiovascular morbidity and mortality. The hallmark of vascular calcification, which involves both media and intima, is represented by the activation of cells committed to an osteogenic programme. Several studies have analysed the role of circulating calcifying cells (CCCs) in vascular calcification. CCCs are bone marrow (BM)-derived cells with an osteogenic phenotype, participating in intima calcification processes and defined by osteocalcin and bone alkaline phosphatase expression. The identification of CCCs in diabetes and atherosclerosis is the most recent, intriguing and yet uncharted chapter in the scenario of the bone-vascular axis. Whether osteogenic shift occurs in the BM, the bloodstream or both, is not known, and also the factors promoting CCC formation have not been identified. However, it is possible to recognize a common pathogenic commitment of inflammation in atherosclerosis and diabetes, in which metabolic control may also have a role. Currently available studies in patients without CKD did not find an association of CCCs with markers of bone metabolism. Preliminary data on CKD patients indicate an implication of mineral bone disease in vascular calcification, as a consequence of functional and anatomic integrity interruption of BM niches. Given the pivotal role that parathyroid hormone and osteoblasts play in regulating expansion, mobilization and homing of haematopoietic stem/progenitors cells, CKD-MBD could promote CCC formation.
Organoid technology provides a revolutionary paradigm toward therapy but has yet to be applied in humans, mainly because of reproducibility and scalability challenges. Here, we overcome these limitations by evolving a scalable organ bud production platform entirely from human induced pluripotent stem cells (iPSC). By conducting massive “reverse” screen experiments, we identified three progenitor populations that can effectively generate liver buds in a highly reproducible manner: hepatic endoderm, endothelium, and septum mesenchyme. Furthermore, we achieved human scalability by developing an omni-well-array culture platform for mass producing homogeneous and miniaturized liver buds on a clinically relevant large scale (>108). Vascularized and functional liver tissues generated entirely from iPSCs significantly improved subsequent hepatic functionalization potentiated by stage-matched developmental progenitor interactions, enabling functional rescue against acute liver failure via transplantation. Overall, our study provides a stringent manufacturing platform for multicellular organoid supply, thus facilitating clinical and pharmaceutical applications especially for the treatment of liver diseases through multi-industrial collaborations.