Cells of the adult human heart.

Cardiovascular disease is the leading cause of death worldwide. Advanced insights into disease mechanisms and therapeutic strategies require a deeper understanding of the molecular processes involved in the healthy heart. Knowledge of the full repertoire of cardiac cells and their gene expression profiles is a fundamental first step in this endeavour. Here, using state-of-the-art analyses of large-scale single-cell and single-nucleus transcriptomes, we characterize six anatomical adult heart regions. Our results highlight the cellular heterogeneity of cardiomyocytes, pericytes and fibroblasts, and reveal distinct atrial and ventricular subsets of cells with diverse developmental origins and specialized properties. We define the complexity of the cardiac vasculature and its changes along the arterio-venous axis. In the immune compartment, we identify cardiac-resident macrophages with inflammatory and protective transcriptional signatures. Furthermore, analyses of cell-to-cell interactions highlight different networks of macrophages, fibroblasts and cardiomyocytes between atria and ventricles that are distinct from those of skeletal muscle. Our human cardiac cell atlas improves our understanding of the human heart and provides a valuable reference for future studies.

Molecular mechanisms underlying therapeutic potential of pericytes.

BACKGROUND: Pericytes are multipotent cells present in every vascularized tissue in the body. Despite the fact that they are well-known for more than a century, pericytes are still representing cells with intriguing properties. This is mainly because of their heterogeneity in terms of definition, tissue distribution, origin, phenotype and multi-functional properties. The body of knowledge illustrates importance of pericytes in the regulation of homeostatic and healing processes in the body. MAIN BODY: In this review, we summarized current knowledge regarding identification, isolation, ontogeny and functional characteristics of pericytes and described molecular mechanisms involved in the crosstalk between pericytes and endothelial or immune cells. We highlighted the role of pericytes in the pathogenesis of fibrosis, diabetes-related complications (retinopathy, nephropathy, neuropathy and erectile dysfunction), ischemic organ failure, pulmonary hypertension, Alzheimer disease, tumor growth and metastasis with the focus on their therapeutic potential in the regenerative medicine. The functions and capabilities of pericytes are impressive and, as yet, incompletely understood. Molecular mechanisms responsible for pericyte-mediated regulation of vascular stability, angiogenesis and blood flow are well described while their regenerative and immunomodulatory characteristics are still not completely revealed. Strong evidence for pericytes' participation in physiological, as well as in pathological conditions reveals a broad potential for their therapeutic use. Recently published results obtained in animal studies showed that transplantation of pericytes could positively influence the healing of bone, muscle and skin and could support revascularization. However, the differences in their phenotype and function as well as the lack of standardized procedure for their isolation and characterization limit their use in clinical trials. CONCLUSION: Critical to further progress in clinical application of pericytes will be identification of tissue specific pericyte phenotype and function, validation and standardization of the procedure for their isolation that will enable establishment of precise clinical settings in which pericyte-based therapy will be efficiently applied.

Connexin 30 is expressed in a subtype of mouse brain pericytes.

Pericytes are mural cells of blood microvessels which play a crucial role at the neurovascular interface of the central nervous system. They are involved in the regulation of blood-brain barrier integrity, angiogenesis, clearance of toxic metabolites, capillary hemodynamic responses, and neuroinflammation, and they demonstrate stem cell activity. Morphological and molecular studies to characterize brain pericytes recently pointed out some heterogeneity in pericyte population. Nevertheless, a clear definition of pericyte subtypes is still lacking. Here, we demonstrate that a fraction of brain pericytes express Connexin 30 (Cx30), a gap junction protein, which, in the brain parenchyma, was thought to be exclusively found in astrocytes. Cx30 could thus be a candidate protein in the composition of the gap junction channels already described between endothelial cells and pericytes. It could also form hemichannels or acts in a channel-independent manner to regulate pericyte morphology, as already observed in astrocytes. Altogether, our results suggest that Cx30 defines a novel brain pericyte subtype.

What's new in regenerative medicine: split up of the mesenchymal stem cell family promises new hope for cardiovascular repair.

Coronary artery disease (CAD) is exceedingly prevalent and requires care optimization. Regenerative medicine holds promise to improve the clinical outcome of CAD patients. Current approach consists in subsidizing the infarcted heart with boluses of autologous stem cells from the bone marrow. Moreover, mesenchymal stem cells (MSCs) are in the focus of intense research owing to an apparent superiority in plasticity and regenerative capacity compared with hematopoietic stem cells. In this review, we report recent findings indicating the presence, within the heterogeneous MSC population, of perivascular stem cells expressing typical pericyte markers. Moreover, we focus on recent research showing the presence of similar cells in the adventitia of large vessels. These discoveries were fundamental to shape a roadmap toward clinical application in patients with myocardial ischemia. Adventitial stem cells are ideal candidates for promotion of cardiac repair owing to their ease of accessibility and expandability and potent vasculogenic activity.

Back to the future: moving beyond "mesenchymal stem cells".

The last decade was dominated by dissemination of the notion that postnatal "mesenchymal stem cells," found primarily in bone marrow but also in other tissues, can generate multiple skeletal and nonskeletal tissues, and thus can be exploited to regenerate a broad range of tissues and organs. The concept of "mesenchymal stem cells" and its applicative implications represent a significant departure from the solidly proven notion that skeletal stem cells are found in the bone marrow (and not in other tissues). Recent data that sharpen our understanding of the identity, nature, origin, and in vivo function of the archetypal "mesenchymal stem cells" (bone marrow skeletal stem cells) point to their microvascular location, mural cell identity, and function as organizers and regulators of the hematopoietic microenvironment/niche. These advances bring back the original concept from which the notion of "mesenchymal stem cells" evolved, and clarify a great deal of experimental data that accumulated in the past decade. As a novel paradigm emerges that accounts for many facets of the biology of skeletal stem cells, a novel paradigm independently emerges for their applicative/translational use. The two paradigms meet each other back in the future.