Several clinical trials of bone marrow stem cell therapy for myocardial infarction are ongoing, but the mechanistic basis for any potential therapeutic effect is currently unclear. A growing body of evidence suggests that the potential improvement in cardiac function is largely independent of cardiac muscle regeneration. A study by Fazel et al. in this issue of the JCI provides evidence that bone marrow–derived c-kit+ cells can lead to an improvement in cardiac function in mutant hypomorphic c-kit mice that is independent of transdifferentiation into either cardiac muscle or endothelial cells, but rather is associated with the release of angiogenic cytokines and associated neovascularization in the infarct border zone (see the related article beginning on page 1865). These findings suggest the potential therapeutic effect of specific paracrine pathways for angiogenesis in improving cardiac function in the injured heart.
Kenneth R. Chien
Adenosine, long known as a regulator of cardiovascular function, has recently been identified as a significant paracrine inhibitor of inflammation that acts primarily by activation of A2A adenosine receptors (A2AARs) on lymphoid or myeloid cells. In this issue of the JCI, Yang et al. describe a proinflammatory phenotype resulting from deletion of the gene encoding the A2B adenosine receptor (A2BAR) in the mouse, suggesting that activation of the A2BAR can also have antiinflammatory effects (see the related article beginning on page 1913). Nevertheless, the role of the A2BAR remains enigmatic since its activation can either stimulate or inhibit the release of proinflammatory cytokines in different cells and tissues.
Joel Linden
Congenital hydrocephalus affects 0.1–0.3% of live births, with a high mortality rate (~50%) in the absence of surgical intervention. Although the insertion of shunts alleviates the symptoms of the majority of congenital cases, the molecular basis of hydrocephalus and the mechanisms of cerebrospinal fluid (CSF) circulation remain largely unknown. Two important players are the subcommissural organ/Reissner’s fiber (SCO/RF) complex and the ventricular ependymal (vel) cells that together facilitate the flow of the CSF through the narrow canals of the ventricular system. In this issue of the JCI, Lang et al. demonstrate that overexpression of the pituitary adenylate cyclase–activating polypeptide (PACAP) type I (PAC1) receptor gene results in abnormal development of the SCO and vel cells, leading to congenital hydrocephalus (see the related article beginning on page 1924). The ligand for the PAC1 receptor is the neuropeptide PACAP, which uncovers what the authors believe to be a novel role for this signaling cascade in the regulation of CSF circulation.
David J. Picketts
Liver X receptors (LXRs) broadly limit cholesterol accumulation by regulating expression of genes involved in cholesterol efflux and storage. In this issue of the JCI, Cummins et al. report that LXRα is involved in similar regulation in the adrenal cortex, but it also substantially modulates glucocorticoid synthesis (see the related article beginning on page 1902). LXRα deletion in mice increases the availability of adrenal cholesterol for steroid synthesis by decreasing the expression of cholesterol efflux transporters. Glucocorticoid synthesis requires intramitochondrial cholesterol transport mediated by the steroidogenic acute regulatory protein (StAR). Surprisingly, LXR deletion and stimulation by an agonist each increase glucocorticoid synthesis. This parallels increased expression of StAR and several other steroidogenic genes.
Colin R. Jefcoate
Predicting the chances of recovery of consciousness and communication in patients who survive their coma but transit in a vegetative state or minimally conscious state (MCS) remains a major challenge for their medical caregivers. Very few studies have examined the slow neuronal changes underlying functional recovery of consciousness from severe chronic brain damage. A case study in this issue of the JCI reports an extraordinary recovery of functional verbal communication and motor function in a patient who remained in MCS for 19 years (see the related article beginning on page 2005). Diffusion tensor MRI showed increased fractional anisotropy (assumed to reflect myelinated fiber density) in posteromedial cortices, encompassing cuneus and precuneus. These same areas showed increased glucose metabolism as studied by PET scanning, likely reflecting the neuronal regrowth paralleling the patient’s clinical recovery. This case shows that old dogmas need to be oppugned, as recovery with meaningful reduction in disability continued in this case for nearly 2 decades after extremely severe traumatic brain injury.
Steven Laureys, Mélanie Boly, Pierre Maquet
Mutations in genes encoding desmosomal proteins have been identified as the major cause of arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC), in which the right ventricle is “replaced” by fibrofatty tissue, resulting in lethal arrhythmias. In this issue of the JCI, Garcia-Gras et al. demonstrate that cardiac-specific loss of the desmosomal protein desmoplakin is sufficient to cause nuclear translocation of plakoglobin, upregulation of adipogenic genes in vitro, and a shift from a cardiomyocyte to an adipocyte cell fate in vivo (see the related article beginning on page 2012). This evidence for potential Wnt/β-catenin signaling defects sets the scene for a comprehensive exploration of the contributions of this pathway to the pathophysiology of ARVC, not only through perturbation of cardiac patterning and development, but also through effects on myocardial differentiation and physiology.
Calum A. MacRae, Walter Birchmeier, Ludwig Thierfelder
Gene therapy is an attractive approach for the treatment of hemophilia, as continuous expression of donated clotting factor VIII (FVIII) DNA would ensure clotting factor replacement at constant circulating levels rather than at the peaks and troughs that characterize the current protein infusion therapeutic approach. In this issue of the JCI, Shi et al. describe an interesting variant of a gene transfer approach for hemophilia (see the related article beginning on page 1974). They show that targeted expression of FVIII in megakaryocytes, with storage in the α-granules of platelets, has the advantage of delivering clotting factors directly to the site of an injury, where platelets accumulate in large numbers and undergo activation accompanied by release of granule contents. Earlier clinical experience with gene transfer into hematopoietic cells highlighted the potential safety risks of this approach, but an F8 transgene may represent a lower risk than transgenes for growth factors or their receptors.
Katherine A. High
Mycolic acids and structures attached to them constitute a major part of the protective envelope of Mycobacterium tuberculosis, and for this reason, their role in tuberculosis pathogenesis has been extensively studied. In this issue of the JCI, Rao et al. examine the effect of trans-cyclopropanation of oxygenated mycolic acids attached to trehalose dimycolate (TDM) on the murine immune response to infection (see the related article beginning on page 1660). Surprisingly, they found that an M. tuberculosis mutant lacking trans-cyclopropane rings was hypervirulent in mice. The recent recognition of a hypervirulence phenotype in mice associated with laboratory and clinical M. tuberculosis strains with altered cell wall components has provided new insights into how M. tuberculosis may establish persistent infection. However, to date, characterization of these bioactive products in pathogenesis has been largely reductionistic; the relationship of their effects observed in mice to the persistent infection and tuberculosis caused by M. tuberculosis observed in humans remains obscure.
Lee W. Riley
A reduced sympathoadrenal response, induced by recent antecedent hypoglycemia, is the key feature of hypoglycemia-associated autonomic failure (HAAF) and, thus, the pathogenesis of iatrogenic hypoglycemia in diabetes. Understanding of the mechanism(s) of that reduced response awaits new insight into its basic molecular, cellular, organ, and whole-body physiology and pathophysiology in experimental models. In this issue of the JCI, McCrimmon and colleagues report that application of urocortin I (a corticotrophin-releasing factor receptor–2 agonist) to the ventromedial hypothalamus reduces the glucose counterregulatory response to hypoglycemia in rats (see the related article beginning on page 1723). Thus, hypothalamic urocortin I release during antecedent hypoglycemia is, among other possibilities, a potential mechanism of HAAF.
Philip E. Cryer
Previous studies using stearoyl-CoA desaturase–1–deficient (SCD1-deficient) mice have shown that this enzyme plays an important role in many diseases of altered cellular metabolism including obesity, insulin resistance, and dyslipidemia. Although SCD1 activity is highest in lipogenic tissues such as the liver and adipose tissue, it is also present at lower levels in most tissues. To better understand the role of SCD1 in liver metabolism it is necessary to explore SCD1 deficiency in a more focused, tissue-specific manner. This commentary focuses on 2 recent studies published in the JCI that address this question using antisense oligonucleotide inhibition of SCD1. First, Jiang et al. have previously reported that long-term inhibition of SCD1 prevents the development of high-fat diet–induced obesity and hepatic steatosis. Second, Gutiérrez-Juárez et al. show in this issue that short-term inhibition of hepatic SCD1 is sufficient to prevent diet-induced hepatic insulin resistance, signifying an important role of hepatic SCD1 in liver insulin sensitivity (see related article beginning on page 1686).
Matthew T. Flowers, Makoto Miyazaki, Xueqing Liu, James M. Ntambi
No posts were found with this tag.