Experimental autoimmune encephalitis and inflammation in the absence of interleukin-12

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Research Article

Authors

Burkhard Becher, Brigit G. Durell, Randolph J. Noelle

T cell homeostatic proliferation elicits effective antitumor autoimmunity

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Research Article

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Wolfgang Dummer, Andreas G. Niethammer, Roberto Baccala, Brian R. Lawson, Norbert Wagner, Ralph A. Reisfeld, Argyrios N. Theofilopoulos

Episodic coronary artery vasospasm and hypertension develop in the absence of Sur2 K_ATP channels

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Research Article

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William A. Chutkow, Jielin Pu, Matthew T. Wheeler, Tomoyuki Wada, Jonathan C. Makielski, Charles F. Burant, Elizabeth M. McNally

Thyroid-stimulating autoantibodies in Graves disease preferentially recognize the free A subunit, not the thyrotropin holoreceptor

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Research Article

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Gregorio D. Chazenbalk, Pavel Pichurin, Chun-Rong Chen, Francesco Latrofa, Alan P. Johnstone, Sandra M. McLachlan, Basil Rapoport

Glucagon-like peptide-1 receptor stimulation increases blood pressure and heart rate and activates autonomic regulatory neurons

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Hiroshi Yamamoto, Charlotte E. Lee, Jacob N. Marcus, Todd D. Williams, J. Michael Overton, Marisol E. Lopez, Anthony N. Hollenberg, Laurie Baggio, Clifford B. Saper, Daniel J. Drucker, Joel K. Elmquist

Immune complex–mediated antigen presentation induces tumor immunity

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Research Article

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Khadija Rafiq, Amy Bergtold, Raphael Clynes

Cyclooxygenase-2 regulates mesenchymal cell differentiation into the osteoblast lineage and is critically involved in bone repair

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Preclinical and clinical studies suggest a possible role for cyclooxygenases in bone repair and create concerns about the use of nonsteroidal antiinflammatory drugs in patients with skeletal injury. We utilized wild-type, COX-1–/–, and COX-2–/– mice to demonstrate that COX-2 plays an essential role in both endochondral and intramembranous bone formation during skeletal repair. The healing of stabilized tibia fractures was significantly delayed in COX-2–/– mice compared with COX-1–/– and wild-type controls. The histology was characterized by a persistence of undifferentiated mesenchyme and a marked reduction in osteoblastogenesis that resulted in a high incidence of fibrous nonunion in the COX-2–/– mice. Similarly, intramembranous bone formation on the calvaria was reduced 60% in COX-2–/– mice following in vivo injection of FGF-1 compared with either COX-1–/– or wild-type mice. To elucidate the mechanism involved in reduced bone formation, osteoblastogenesis was studied in bone marrow stromal cell cultures obtained from COX-2–/– and wild-type mice. Bone nodule formation was reduced 50% in COX-2–/– mice. The defect in osteogenesis was completely rescued by addition of prostaglandin E2 (PGE2) to the cultures. In the presence of bone morphogenetic protein (BMP-2), bone nodule formation was enhanced to a similar level above that observed with PGE2 alone in both control and COX-2–/– cultures, indicating that BMPs complement COX-2 deficiency and are downstream of prostaglandins. Furthermore, we found that the defect in COX-2–/– cultures correlated with significantly reduced levels of cbfa1 and osterix, two genes necessary for bone formation. Addition of PGE2 rescued this defect, while BMP-2 enhanced cbfa1 and osterix in both COX-2–/– and wild-type cultures. Finally, the effects of these agents were additive, indicating that COX-2 is involved in maximal induction of osteogenesis. These results provide a model whereby COX-2 regulates the induction of cbfa1 and osterix to mediate normal skeletal repair.

Authors

Xinping Zhang, Edward M. Schwarz, Donald A. Young, J. Edward Puzas, Randy N. Rosier, Regis J. O’Keefe

Multipotent adult progenitor cells from bone marrow differentiate into functional hepatocyte-like cells

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Abstract

We have derived from normal human, mouse, and rat postnatal bone marrow primitive, multipotent adult progenitor cells (MAPCs) that can differentiate into most mesodermal cells and neuroectodermal cells in vitro and into all embryonic lineages in vivo. Here, we show that MAPCs can also differentiate into hepatocyte-like cells in vitro. Human, mouse, and rat MAPCs, cultured on Matrigel with FGF-4 and HGF, differentiated into epithelioid cells that expressed hepatocyte nuclear factor-3β (HNF-3β), GATA4, cytokeratin 19 (CK19), transthyretin, and α-fetoprotein by day 7, and expressed CK18, HNF-4, and HNF-1α on days 14–28. Virtually all human, as well as a majority of rodent cells stained positive for albumin and CK18 on day 21; 5% (rodent) to 25% (human) cells were binucleated by day 21. These cells also acquired functional characteristics of hepatocytes: they secreted urea and albumin, had phenobarbital-inducible cytochrome p450, could take up LDL, and stored glycogen. MAPCs, which can be expanded in vitro and maintained in an undifferentiated state for more than 100 population doublings, can thus differentiate into cells with morphological, phenotypic, and functional characteristics of hepatocytes. MAPCs may therefore be an ideal cell for in vivo therapies for liver disorders or for use in bioartificial liver devices.

Authors

Robert E. Schwartz, Morayma Reyes, Lisa Koodie, Yuehua Jiang, Mark Blackstad, Troy Lund, Todd Lenvik, Sandra Johnson, Wei-Shou Hu, Catherine M. Verfaillie