Browsing by Author "Regan, Jenna N."

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    Differentiated Smooth Muscle Cells Generate a Subpopulation of Resident Vascular Progenitor Cells in the Adventitia Regulated by Klf4
    (American Heart Association, 2017-01-20) Majesky, Mark W.; Horita, Henrick; Ostriker, Allison; Lu, Sizhao; Regan, Jenna N.; Bagchi, Ashim; Dong, Xiu Rong; Poczobutt, Joanna; Nemenoff, Raphael A.; Weiser-Evans, Mary C.M.; Medicine, School of Medicine
    RATIONALE: The vascular adventitia is a complex layer of the vessel wall consisting of vasa vasorum microvessels, nerves, fibroblasts, immune cells, and resident progenitor cells. Adventitial progenitors express the stem cell markers, Sca1 and CD34 (adventitial sca1-positive progenitor cells [AdvSca1]), have the potential to differentiate in vitro into multiple lineages, and potentially contribute to intimal lesions in vivo. OBJECTIVE: Although emerging data support the existence of AdvSca1 cells, the goal of this study was to determine their origin, degree of multipotency and heterogeneity, and contribution to vessel remodeling. METHODS AND RESULTS: Using 2 in vivo fate-mapping approaches combined with a smooth muscle cell (SMC) epigenetic lineage mark, we report that a subpopulation of AdvSca1 cells is generated in situ from differentiated SMCs. Our data establish that the vascular adventitia contains phenotypically distinct subpopulations of progenitor cells expressing SMC, myeloid, and hematopoietic progenitor-like properties and that differentiated SMCs are a source to varying degrees of each subpopulation. SMC-derived AdvSca1 cells exhibit a multipotent phenotype capable of differentiating in vivo into mature SMCs, resident macrophages, and endothelial-like cells. After vascular injury, SMC-derived AdvSca1 cells expand in number and are major contributors to adventitial remodeling. Induction of the transcription factor Klf4 in differentiated SMCs is essential for SMC reprogramming in vivo, whereas in vitro approaches demonstrate that Klf4 is essential for the maintenance of the AdvSca1 progenitor phenotype. CONCLUSIONS: We propose that generation of resident vascular progenitor cells from differentiated SMCs is a normal physiological process that contributes to the vascular stem cell pool and plays important roles in arterial homeostasis and disease.
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    Osteocyte-Intrinsic TGF-β Signaling Regulates Bone Quality through Perilacunar/Canalicular Remodeling
    (Elsevier, 2017-11-28) Dole, Neha S.; Mazur, Courtney M.; Acevedo, Claire; Lopez, Justin P.; Monteiro, David A.; Fowler, Tristan W.; Gludovatz, Bernd; Walsh, Flynn; Regan, Jenna N.; Messina, Sara; Evans, Daniel S.; Lang, Thomas F.; Zhang, Bin; Ritchie, Robert O.; Mohammad, Khalid S.; Alliston, Tamara; Medicine, School of Medicine
    Summary Poor bone quality contributes to bone fragility in diabetes, aging, and osteogenesis imperfecta. However, the mechanisms controlling bone quality are not well understood, contributing to the current lack of strategies to diagnose or treat bone quality deficits. Transforming growth factor beta (TGF-β) signaling is a crucial mechanism known to regulate the material quality of bone, but its cellular target in this regulation is unknown. Studies showing that osteocytes directly remodel their perilacunar/canalicular matrix led us to hypothesize that TGF-β controls bone quality through perilacunar/canalicular remodeling (PLR). Using inhibitors and mice with an osteocyte-intrinsic defect in TGF-β signaling (TβRIIocy−/−), we show that TGF-β regulates PLR in a cell-intrinsic manner to control bone quality. Altogether, this study emphasizes that osteocytes are key in executing the biological control of bone quality through PLR, thereby highlighting the fundamental role of osteocyte-mediated PLR in bone homeostasis and fragility.
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    Osteolytic Breast Cancer Causes Skeletal Muscle Weakness in an Immunocompetent Syngeneic Mouse Model
    (Frontiers Media, 2017-12-19) Regan, Jenna N.; Mikesell, Carter; Reiken, Steven; Xu, Haifang; Marks, Andrew R.; Mohammad, Khalid S.; Guise, Theresa A.; Waning, David L.; Medicine, School of Medicine
    Muscle weakness and cachexia are significant paraneoplastic syndromes of many advanced cancers. Osteolytic bone metastases are common in advanced breast cancer and are a major contributor to decreased survival, performance, and quality of life for patients. Pathologic fracture caused by osteolytic cancer in bone (OCIB) leads to a significant (32%) increased risk of death compared to patients without fracture. Since muscle weakness is linked to risk of falls which are a major cause of fracture, we have investigated skeletal muscle response to OCIB. Here, we show that a syngeneic mouse model of OCIB (4T1 mammary tumor cells) leads to cachexia and skeletal muscle weakness associated with oxidation of the ryanodine receptor and calcium (Ca2+) release channel (RyR1). Muscle atrophy follows known pathways via both myostatin signaling and expression of muscle-specific ubiquitin ligases, atrogin-1 and MuRF1. We have identified a mechanism for skeletal muscle weakness due to increased oxidative stress on RyR1 via NAPDH oxidases [NADPH oxidase 2 (Nox2) and NADPH oxidase 4 (Nox4)]. In addition, SMAD3 phosphorylation is higher in muscle from tumor-bearing mice, a critical step in the intracellular signaling pathway that transmits TGFβ signaling to the nucleus. This is the first time that skeletal muscle weakness has been described in a syngeneic model of OCIB and represents a unique model system in which to study cachexia and changes in skeletal muscle.
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    The P2Y2 nucleotide receptor is an inhibitor of vascular calcification
    (Elsevier, 2017-02) Qian, Shaomin; Regan, Jenna N.; Shelton, Maxwell T.; Hoggatt, April; Mohammad, Khalid S.; Herring, Paul B.; Seye, Cheikh I.; Cellular and Integrative Physiology, School of Medicine
    BACKGROUND AND AIMS: Mutations in the 5'-nucleotidase ecto (NT5E) gene that encodes CD73, a nucleotidase that converts AMP to adenosine, are linked to arterial calcification. However, the role of purinergic receptor signaling in the pathology of intimal calcification is not well understood. In this study, we examined whether extracellular nucleotides acting via P2Y2 receptor (P2Y2R) modulate arterial intimal calcification, a condition highly correlated with cardiovascular morbidity. METHODS: Apolipoprotein E, P2Y2R double knockout mice (ApoE-/-P2Y2R-/-) were used to determine the effect of P2Y2R deficiency on vascular calcification in vivo. Vascular smooth muscle cells (VSMC) isolated from P2Y2R-/- mice grown in high phosphate medium were used to assess the role of P2Y2R in the conversion of VSMC into osteoblasts. Luciferase-reporter assays were used to assess the effect of P2Y2R on the transcriptional activity of Runx2. RESULTS: P2Y2R deficiency in ApoE-/- mice caused extensive intimal calcification despite a significant reduction in atherosclerosis and macrophage plaque content. The ectoenzyme apyrase that degrades nucleoside di- and triphosphates accelerated high phosphate-induced calcium deposition in cultured VSMC. Expression of P2Y2R inhibits calcification in vitro inhibited the osteoblastic trans-differentiation of VSMC. Mechanistically, expression of P2Y2R inhibited Runx2 transcriptional activation of an osteocalcin promoter driven luciferase reporter gene. CONCLUSIONS: This study reveals a role for vascular P2Y2R as an inhibitor of arterial intimal calcification and provides a new mechanistic insight into the regulation of the osteoblastic trans-differentiation of SMC through P2Y2R-mediated Runx2 antagonism. Given that calcification of atherosclerotic lesions is a significant clinical problem, activating P2Y2R may be an effective therapeutic approach for treatment or prevention of vascular calcification.
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    The Role of TGFβ in Bone-Muscle Crosstalk
    (Springer, 2017-02) Regan, Jenna N.; Trivedi, Trupti; Guise, Theresa A.; Waning, David L.; Department of Medicine, School of Medicine
    Purpose of Review The role of bone-derived factors in regulation of skeletal muscle function is an important emerging aspect of research into bone-muscle crosstalk. Implications for this area of research are far reaching and include understanding skeletal muscle weakness in cancer, osteoporosis, cachexia, rare diseases of bone, and aging. Recent Findings Recent research shows that bone-derived factors can lead to changes in the skeletal muscle. These changes can either be anabolic or catabolic, and we focus this review on the role of TGFβ in driving oxidative stress and skeletal muscle weakness in the setting of osteolytic cancer in the bone. Summary The bone is a preferred site for breast cancer metastasis and leads to pathological bone loss. Osteolytic cancer in the bone leads to release of TGFβ from the bone via osteoclast-mediated bone destruction. Our appreciation of crosstalk between the muscle and bone has recently expanded beyond mechanical force-driven events to encompass a variety of signaling factors originating in one tissue and communicating to the other. This review summarizes some previously known mediators of bone-to-muscle signaling and also recent work identifying a new role for bone-derived TGFβ as a cause of skeletal muscle weakness in the setting of osteolytic cancer in the bone. Multiple points of potential therapeutic intervention are discussed.
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    Skeletal muscle Ca2+ mishandling: another effect of bone-to-muscle signaling
    (Elsevier, 2016-01) Regan, Jenna N.; Waning, David L.; Guise, Theresa A.; Department of Medicine, IU School of Medicine
    Our appreciation of crosstalk between muscle and bone has recently expanded beyond mechanical force-driven events to encompass a variety of signaling factors originating in one tissue and communicating to the other. While the recent identification of new ‘myokines’ has shifted some focus to the role of muscle in this partnership, bone-derived factors and their effects on skeletal muscle should not be overlooked. This review summarizes some previously known mediators of bone-to-muscle signaling and also recent work identifying a new role for bone-derived TGF-β as a cause of skeletal muscle weakness in the setting of cancer-induced bone destruction. Oxidation of the ryanodine receptor/calcium release channel (RyR1) in skeletal muscle occurs via a TGF-β-Nox4-RyR1 axis and leads to calcium mishandling and decreased muscle function. Multiple points of potential therapeutic intervention were identified, from preventing the bone destruction to stabilizing the RYR1 calcium channel. This new data reinforces the concept that bone can be an important source of signaling factors in pathphysiological settings.