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Pericytes are tissue-resident mesenchymal progenitor cells anatomically associated with the vasculature that have been shown to participate in tissue regeneration. Here, we tested the hypothesis that kidney pericytes, derived from FoxD1+ mesodermal progenitors during embryogenesis, are necessary for postnatal kidney homeostasis. Diphtheria toxin delivery to FoxD1Cre::RsDTR transgenic mice resulted in selective ablation of >90% of kidney pericytes but not other cell lineages. Abrupt increases in plasma creatinine, blood urea nitrogen, and albuminuria within 96 h indicated acute kidney injury in pericyte-ablated mice. Loss of pericytes led to a rapid accumulation of neutral lipid vacuoles, swollen mitochondria, and apoptosis in tubular epithelial cells. Pericyte ablation led to endothelial cell swelling, reduced expression of vascular homeostasis markers, and peritubular capillary loss. Despite the observed injury, no signs of the acute inflammatory response were observed. Pathway enrichment analysis of genes expressed in kidney pericytes in vivo identified basement membrane proteins, angiogenic factors, and factors regulating vascular tone as major regulators of vascular function. Using novel microphysiological devices, we recapitulated human kidney peritubular capillaries coated with pericytes and showed that pericytes regulate permeability, basement membrane deposition, and microvascular tone. These findings suggest that through the active support of the microvasculature, pericytes are essential to adult kidney homeostasis. [ABSTRACT FROM AUTHOR]

Recent research has highlighted the importance of bone and muscle interactions during development and regeneration. There still remains, however, a large gap in the current understanding of the cells and mechanisms involved in this interplay. In particular, how muscle-derived cells, specifically mesenchymal stromal cells (MSCs), can impact bone regeneration or lead to pathologic ectopic bone formation is unclear. Here, a review is given of the evidence supporting the contribution of muscle-derived MSC to bone regeneration and suggesting a critical role for the inflammatory milieu. This article is part of a Special Issue entitled “Muscle Bone Interactions”. [ABSTRACT FROM AUTHOR]

Depending on the inflammatory milieu, injury can result either in a tissue's complete regeneration or in its degeneration and fibrosis, the latter of which could potentially lead to permanent organ failure. Yet how inflammatory cells regulate matrix-producing cells involved in the reparative process is unknown. Here we show that in acutely damaged skeletal muscle, sequential interactions between multipotent mesenchymal progenitors and infiltrating inflammatory cells determine the outcome of the reparative process. We found that infiltrating inflammatory macrophages, through their expression of tumor necrosis factor (TNF), directly induce apoptosis of fibro/adipogenic progenitors (FAPs). In states of chronic damage, however, such as those in mdx mice, macrophages express high levels of transforming growth factor β1 (TGF-β1), which prevents the apoptosis of FAPs and induces their differentiation into matrix-producing cells. Treatment with nilotinib, a kinase inhibitor with proposed anti-fibrotic activity, can block the effect of TGF-β1 and reduce muscle fibrosis in mdx mice. Our findings reveal an unexpected anti-fibrotic role of TNF and suggest that disruption of the precisely timed progression from a TNF-rich to a TGF-β−rich environment favors fibrotic degeneration of the muscle during chronic injury. [ABSTRACT FROM AUTHOR]

Adult stem cells are activated to proliferate and differentiate during normal tissue homeostasis as well as in disease states and injury. This activation is a vital component in the restoration of function to damaged tissue via either complete or partial regeneration. When regeneration does not fully occur, reparative processes involving an overproduction of stromal components ensure the continuity of tissue at the expense of its normal structure and function, resulting in a "reparative disorder". Adult stem cells from multiple organs have been identified as being involved in this process and their role in tissue repair is being investigated. Evidence for the participation of mesenchymal stromal cells (MSCs) in the tissue repair process across multiple tissues is overwhelming and their role in reparative disorders is clearly demonstrated, as is the involvement of a number of specific signaling pathways. Transforming growth factor beta, bone morphogenic protein and Wnt pathways interact to form a complex signaling network that is critical in regulating the fate choices of both stromal and tissue-specific resident stem cells (TSCs), determining whether functional regeneration or the formation of scar tissue follows an injury. A growing understanding of both TSCs, MSCs and the complex cascade of signals regulating both cell populations have, therefore, emerged as potential therapeutic targets to treat reparative disorders. This review focuses on recent advances on the role of these cells in skeletal muscle, heart and lung tissues. [ABSTRACT FROM AUTHOR]

Abstract: Recent studies have shown that circadian clock genes are expressed in various peripheral tissues, raising the possibility that multiple clocks regulate circadian physiology. To study clock gene expression in the rhesus macaque pituitary gland we used gene microarray data and found that the pituitary glands of young and old adult males express several components of the circadian clock (Per1, Per2, Cry1, Bmal1, Clock, Rev-erbα and Csnk1ɛ). Semi-quantitative reverse-transcription polymerase chain reaction (sqRT-PCR) confirmed the presence of these core-clock genes and detected significant age-related differences in the expression of Per2. sqRT-PCR also showed differential expression of core-clock genes at two opposing time-points over the 24-h day, with greater expression of Per2 and Bmal1 (P <0.05) at 1300h as compared to 0100h. Immunohistochemistry revealed rhythmic expression of REV-ERBα in the pituitary glands of female macaques. These data provide evidence that the rhesus macaque pituitary gland expresses core-clock genes and their associated protein products in a 24-h rhythmic pattern, and that their expression is moderately impacted by aging processes. [Copyright &y& Elsevier]

Abstract: The development of species-specific gene microarrays has greatly facilitated gene expression profiling in nonhuman primates. However, to obtain accurate and physiologically meaningful data from these microarrays, one needs to consider several factors when designing the studies. This article focuses on effective experimental design while the companion article focuses on methodology and data analysis. Biological cycles have a major influence on gene expression, and at least 10% of the expressed genes are likely to show a 24-h expression pattern. Consequently, the time of day when RNA samples are collected can influence detection of significant changes in gene expression levels. Similarly, when photoperiodic species such as the rhesus macaque are housed outdoors, some of their genes show differential expression according to the time of year. In addition, the sex-steroid environment of humans and many nonhuman primates changes markedly across the menstrual cycle, and so phase of the cycle needs to be considered when studying gene expression in adult females. [Copyright &y& Elsevier]

Although the immune response within draining lymph nodes (DLNs) has been studied for decades, how their stromal compartment contributes to this process remains to be fully explored. Here, we show that donor mast cells were prominent activators of collagen I deposition by fibroblastic reticular cells (FRCs) in DLNs shortly following transplantation. Serial analysis of the DLN indicated that the LN stroma did not return to its baseline microarchitecture following organ rejection and that the DLN contained significant fibrosis following repetitive organ transplants. Using several FRC conditional-knockout mice, we show that induction of senescence in the FRCs of the DLN resulted in massive production of collagen I and a proinflammatory milieu within the DLN. Stimulation of herpes virus entry mediator (HVEM) on FRCs by its ligand LIGHT contributed chiefly to the induction of senescence in FRCs and overproduction of collagen I. Systemic administration of ex vivo-expanded FRCs to mice decreased DLN fibrosis and strengthened the effect of anti-CD40L in prolonging heart allograft survival. These data demonstrate that the transformation of FRCs into proinflammatory myofibroblasts is critically important for the maintenance of a proinflammatory milieu within a fibrotic DLN. [ABSTRACT FROM AUTHOR]

The cellular substrate underlying aberrant craniofacial connective tissue accumulation that occurs in disorders such as congenital infiltration of the face (CILF) remain elusive. Here we analyze the in vivo properties of a recently identified population of neural crest-derived CD31-:CD45-:alpha7-:Sca1+:PDGFRa+ fibro/adipogenic progenitors (NCFAPs). In serial transplantation experiments in which NCFAPs were prospectively purified and transplanted into wild type mice, NCFAPs were found to be capable of self-renewal while keeping their adipogenic potential. NCFAPs constitute the main responsive FAP fraction following acute masseter muscle damage, surpassing the number of mesoderm-derived FAPs (MFAPs) during the regenerative response. Lastly, NCFAPs differentiate into adipocytes during muscle regeneration in response to pro-adipogenic systemic cues. Altogether our data indicate that NCFAPs are a population of stem/primitive progenitor cells primarily involved in craniofacial muscle regeneration that can cause tissue degeneration when the damage co-occurs with an obesity inducing diet. [ABSTRACT FROM AUTHOR]