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1. Integrin Activation Controls Regulatory T Cell–Mediated Peripheral Tolerance

Author

Klann, Jane E, Kim, Stephanie H, Remedios, Kelly A, He, Zhaoren, Metz, Patrick J, Lopez, Justine, Tysl, Tiffani, Olvera, Jocelyn G, Ablack, Jailal N, Cantor, Joseph M, Boland, Brigid S, Yeo, Gene, Zheng, Ye, Lu, Li-Fan, Bui, Jack D, Ginsberg, Mark H, Petrich, Brian G, and Chang, John T

Subjects
Biochemistry and Cell Biology, Biological Sciences, Prevention, Autoimmune Disease, Aetiology, 1.1 Normal biological development and functioning, Underpinning research, 2.1 Biological and endogenous factors, Inflammatory and immune system, Animals, Autoimmunity, Inflammation, Integrins, Mice, Peripheral Tolerance, T-Lymphocytes, Regulatory, Talin, Transcriptome, Immunology, Biochemistry and cell biology
Abstract

Maintenance of the regulatory T (Treg) cell pool is essential for peripheral tolerance and prevention of autoimmunity. Integrins, heterodimeric transmembrane proteins consisting of α and β subunits that mediate cell-to-cell and cell-to-extracellular matrix interactions, play an important role in facilitating Treg cell contact-mediated suppression. In this article, we show that integrin activation plays an essential, previously unappreciated role in maintaining murine Treg cell function. Treg cell-specific loss of talin, a β integrin-binding protein, or expression of talin(L325R), a mutant that selectively abrogates integrin activation, resulted in lethal systemic autoimmunity. This dysfunction could be attributed, in part, to a global dysregulation of the Treg cell transcriptome. Activation of integrin α4β1 led to increased suppressive capacity of the Treg cell pool, suggesting that modulating integrin activation on Treg cells may be a useful therapeutic strategy for autoimmune and inflammatory disorders. Taken together, these results reveal a critical role for integrin-mediated signals in controlling peripheral tolerance by virtue of maintaining Treg cell function.

Published
2018

2. Talin Plays a Critical Role in the Maintenance of the Regulatory T Cell Pool

Author

Klann, Jane E, Remedios, Kelly A, Kim, Stephanie H, Metz, Patrick J, Lopez, Justine, Mack, Lauren A, Zheng, Ye, Ginsberg, Mark H, Petrich, Brian G, and Chang, John T

Subjects
Underpinning research, 2.1 Biological and endogenous factors, 1.1 Normal biological development and functioning, Aetiology, Inflammatory and immune system, Animals, Apoptosis, Dendritic Cells, Genes, bcl-2, Homeostasis, Interleukin-2, Interleukin-2 Receptor alpha Subunit, Lymphocyte Activation, Lymphocyte Function-Associated Antigen-1, Mice, Myeloid Cell Leukemia Sequence 1 Protein, Signal Transduction, T-Lymphocytes, Regulatory, Talin, Immunology
Abstract

Talin, a cytoskeletal protein essential in mediating integrin activation, has been previously shown to be involved in the regulation of T cell proliferation and function. In this study, we describe a role for talin in maintaining the homeostasis and survival of the regulatory T (Treg) cell pool. T cell-specific deletion of talin in Tln1fl/flCd4Cre mice resulted in spontaneous lymphocyte activation, primarily due to numerical and functional deficiencies of Treg cells in the periphery. Peripheral talin-deficient Treg cells were unable to maintain high expression of IL-2Rα, resulting in impaired IL-2 signaling and ultimately leading to increased apoptosis through downregulation of prosurvival proteins Bcl-2 and Mcl-1. The requirement for talin in maintaining high IL-2Rα expression by Treg cells was due, in part, to integrin LFA-1-mediated interactions between Treg cells and dendritic cells. Collectively, our data suggest a critical role for talin in Treg cell-mediated maintenance of immune homeostasis.

Published
2017

3. Downregulation of 26S proteasome catalytic activity promotes epithelial-mesenchymal transition

Author

Banno, Asoka, Garcia, Daniel A, van Baarsel, Eric D, Metz, Patrick J, Fisch, Kathleen, Widjaja, Christella E, Kim, Stephanie H, Lopez, Justine, Chang, Aaron N, Geurink, Paul P, Florea, Bogdan I, Overkleeft, Hermen S, Ovaa, Huib, Bui, Jack D, Yang, Jing, and Chang, John T

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Breast Cancer, Stem Cell Research - Nonembryonic - Non-Human, Stem Cell Research - Nonembryonic - Human, Stem Cell Research, Cancer, 2.1 Biological and endogenous factors, Aetiology, Animals, Biocatalysis, Breast Neoplasms, Carcinogenesis, Cell Line, Cell Line, Transformed, Down-Regulation, Epithelial-Mesenchymal Transition, Female, Gene Expression Profiling, Humans, Kaplan-Meier Estimate, Mice, Nude, Neoplastic Stem Cells, Proteasome Endopeptidase Complex, Proteasome Inhibitors, Transplantation, Heterologous, EMT, proteasome, TGF-beta, cancer stem cells, Oncology and carcinogenesis
Abstract

The epithelial-mesenchymal transition (EMT) endows carcinoma cells with phenotypic plasticity that can facilitate the formation of cancer stem cells (CSCs) and contribute to the metastatic cascade. While there is substantial support for the role of EMT in driving cancer cell dissemination, less is known about the intracellular molecular mechanisms that govern formation of CSCs via EMT. Here we show that β2 and β5 proteasome subunit activity is downregulated during EMT in immortalized human mammary epithelial cells. Moreover, selective proteasome inhibition enabled mammary epithelial cells to acquire certain morphologic and functional characteristics reminiscent of cancer stem cells, including CD44 expression, self-renewal, and tumor formation. Transcriptomic analyses suggested that proteasome-inhibited cells share gene expression signatures with cells that have undergone EMT, in part, through modulation of the TGF-β signaling pathway. These findings suggest that selective downregulation of proteasome activity in mammary epithelial cells can initiate the EMT program and acquisition of a cancer stem cell-like phenotype. As proteasome inhibitors become increasingly used in cancer treatment, our findings highlight a potential risk of these therapeutic strategies and suggest a possible mechanism by which carcinoma cells may escape from proteasome inhibitor-based therapy.

Published
2016

4. Immunodeficiency and Autoimmune Enterocolopathy Linked to NFAT5 Haploinsufficiency

Author

Boland, Brigid S, Widjaja, Christella E, Banno, Asoka, Zhang, Bing, Kim, Stephanie H, Stoven, Samantha, Peterson, Michael R, Jones, Marilyn C, Su, H Irene, Crowe, Sheila E, Bui, Jack D, Ho, Samuel B, Okugawa, Yoshinaga, Goel, Ajay, Marietta, Eric V, Khosroheidari, Mahdieh, Jepsen, Kristen, Aramburu, Jose, López-Rodríguez, Cristina, Sandborn, William J, Murray, Joseph A, Harismendy, Olivier, and Chang, John T

Subjects
Biomedical and Clinical Sciences, Immunology, Rare Diseases, Clinical Research, Autoimmune Disease, 2.1 Biological and endogenous factors, Aetiology, Inflammatory and immune system, Animals, Autoimmune Diseases, CD8-Positive T-Lymphocytes, Cells, Cultured, Cytokines, DNA Mutational Analysis, Gastrointestinal Diseases, Gene Expression, Haploinsufficiency, Humans, Immunoblotting, Immunologic Deficiency Syndromes, Jurkat Cells, Killer Cells, Natural, Male, Mice, 129 Strain, Mice, Knockout, Reverse Transcriptase Polymerase Chain Reaction, Transcription Factors, Young Adult, Biochemistry and cell biology
Abstract

The link between autoimmune diseases and primary immunodeficiency syndromes has been increasingly appreciated. Immunologic evaluation of a young man with autoimmune enterocolopathy and unexplained infections revealed evidence of immunodeficiency, including IgG subclass deficiency, impaired Ag-induced lymphocyte proliferation, reduced cytokine production by CD8(+) T lymphocytes, and decreased numbers of NK cells. Genetic evaluation identified haploinsufficiency of NFAT5, a transcription factor regulating immune cell function and cellular adaptation to hyperosmotic stress, as a possible cause of this syndrome. Inhibition or deletion of NFAT5 in normal human and murine cells recapitulated several of the immune deficits identified in the patient. These results provide evidence of a primary immunodeficiency disorder associated with organ-specific autoimmunity linked to NFAT5 deficiency.

Published
2015

5. miR-142 controls metabolic reprogramming that regulates dendritic cell activation

Author

Sun, Yaping, Oravecz-Wilson, Katherine, Bridges, Sydney, McEachin, Richard, Wu, Julia, Kim, Stephanie H., Taylor, Austin, Zajac, Cynthia, Fujiwara, Hideaki, Peltier, Daniel Christopher, Saunders, Thomas, and Reddy, Pavan

Subjects
MicroRNA -- Research, Oxidation-reduction reactions -- Research, Glucose metabolism -- Research, Dendritic cells -- Research, T cells -- Research, Cytokines, Immune response, Infection, Fatty acids, Carnitine, Health care industry
Abstract

DCs undergo metabolic reprogramming from a predominantly oxidative phosphorylation (OXPHOS) to glycolysis to mount an immunogenic response. The mechanism underpinning the metabolic reprogramming remains elusive. We demonstrate that miRNA-142 (miR-142) is pivotal for this shift in metabolism, which regulates the tolerogenic and immunogenic responses of DCs. In the absence of miR-142, DCs fail to switch from OXPHOS and show reduced production of proinflammatory cytokines and the ability to activate T cells in vitro and in in vivo models of sepsis and alloimmunity. Mechanistic studies demonstrate that miR-142 regulates fatty acid (FA) oxidation, which causes the failure to switch to glycolysis. Loss- and gain-of- function experiments identified carnitine palmitoyltransferase -1a (CPT1a), a key regulator of the FA pathway, as a direct target of miR142 that is pivotal for the metabolic switch. Thus, our findings show that miR-142 is central to the metabolic reprogramming that specifically favors glycolysis and immunogenic response by DCs., Introduction DCs regulate both immunogenic and tolerogenic responses (1, 2). Metabolic processes are key to determining the functional fate of DCs upon activation (3-7). A shift toward glycolysis and the [...]

Published
2019
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7. Correction: BMP9-regulated angiogenic signaling plays an important role in the osteogenic differentiation of mesenchymal progenitor cells

Author

Hu, Ning, primary, Jiang, Dianming, additional, Huang, Enyi, additional, Liu, Xing, additional, Li, Ruidong, additional, Liang, Xi, additional, Kim, Stephanie H., additional, Chen, Xiang, additional, Gao, Jian-Li, additional, Zhang, Hongyu, additional, Zhang, Wenwen, additional, Kong, Yu-Han, additional, Zhang, Jiye, additional, Wang, Jinhua, additional, Shui, Wei, additional, Luo, Xiaoji, additional, Liu, Bo, additional, Cui, Jing, additional, Rose Rogers, Mary, additional, Shen, Jikun, additional, Zhao, Chen, additional, Wang, Ning, additional, Wu, Ningning, additional, Luu, Hue H., additional, Haydon, Rex C., additional, He, Tong-Chuan, additional, and Huang, Wei, additional

Published
2023
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8. Supplementary Data from Synergistic Antitumor Effect of the Activated PPARγ and Retinoid Receptors on Human Osteosarcoma

Author

He, Bai-Cheng, primary, Chen, Liang, primary, Zuo, Guo-Wei, primary, Zhang, Wenli, primary, Bi, Yang, primary, Huang, Jiayi, primary, Wang, Yi, primary, Jiang, Wei, primary, Luo, Qing, primary, Shi, Qiong, primary, Zhang, Bing-Qiang, primary, Liu, Bo, primary, Lei, Xia, primary, Luo, Jinyong, primary, Luo, Xiaoji, primary, Wagner, Eric R., primary, Kim, Stephanie H., primary, He, Connie J., primary, Hu, Yawen, primary, Shen, Jikun, primary, Zhou, Qixin, primary, Rastegar, Farbod, primary, Deng, Zhong-Liang, primary, Luu, Hue H., primary, He, Tong-Chuan, primary, and Haydon, Rex C., primary

Published
2023
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10. Proteasome activity regulates [CD8.sup.+] T lymphocyte metabolism and fate specification

Author

Widjaja, Christella E., Olvera, Jocelyn G., Metz, Patrick J., Phan, Anthony T., Savas, Jeffrey N., de Bruin, Gerjan, Leestemaker, Yves, Berkers, Celia R., de Jong, Annemieke, Florea, Bogdan I., Fisch, Kathleen, Lopez, Justine, Kim, Stephanie H., Garcia, Daniel A., Searles, Stephen, Bui, Jack D., Chang, Aaron N., Yates, John R., III, Goldrath, Ananda W., Overkleeft, Hermen S., Ovaa, Huib, and Chang, John T.

Subjects
Ubiquitin-proteasome system -- Health aspects, Metabolism -- Observations, T cells -- Health aspects, Health care industry
Abstract

During an immune response, [CD8.sup.+] T lymphocytes can undergo asymmetric division, giving rise to daughter cells that exhibit distinct tendencies to adopt terminal effector and memory cell fates. Here we show that 'pre-effector' and 'pre-memory' cells resulting from the first [CD8.sup.+] T cell division in vivo exhibited low and high rates of endogenous proteasome activity, respectively. Pharmacologic reduction of proteasome activity in [CD8.sup.+] T cells early during differentiation resulted in acquisition of terminal effector cell characteristics, whereas enhancement of proteasome activity conferred attributes of memory lymphocytes. Transcriptomic and proteomic analyses revealed that modulating proteasome activity in [CD8.sup.+] T cells affected cellular metabolism. These metabolic changes were mediated, in part, through differential expression of Myc, a transcription factor that controls glycolysis and metabolic reprogramming. Taken together, these results demonstrate that proteasome activity is an important regulator of [CD8.sup.+] T cell fate and raise the possibility that increasing proteasome activity may be a useful therapeutic strategy to enhance the generation of memory lymphocytes., Introduction In response to microbial infection, [CD8.sup.+] T lymphocytes undergo rapid clonal proliferation associated with differentiation into terminal effector and memory cell subsets. Terminally differentiated, short-lived effector cells produce inflammatory [...]

Published
2017
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16. Von Hippel-Lindau disease-associated hemangioblastomas are derived from embryologic multipotent cells

Author

Park, Deric M., Zhuang, Zhengping, Chen, Ling, Szerlip, Nicholas, Maric, Irina, Li, Jie, Sohn, Taesung, Kim, Stephanie H., Lubensky, Irina A., Vortmeyer, Alexander O., Rodgers, Griffin P., Oldfield, Edward H., and Lonser, Russell R.

Subjects
Von Hippel-Lindau disease -- Complications and side effects, Von Hippel-Lindau disease -- Research, Nervous system cancer -- Risk factors, Nervous system cancer -- Research
Abstract

ABSTRACT Background To determine the origin of the neoplastic cell in central nervous system (CNS) hemangioblastomas in von Hippel-Lindau disease (VHL) and its role in tumor formation and distribution, we [...]

Published
2007

17. Cross-talk between EGF and BMP9 signalling pathways regulates the osteogenic differentiation of mesenchymal stem cells

Author

Liu, Xing, Qin, Jiaqiang, Luo, Qing, Bi, Yang, Zhu, Gaohui, Jiang, Wei, Kim, Stephanie H., Li, Mi, Su, Yuxi, Nan, Guoxin, Cui, Jing, Zhang, Wenwen, Li, Ruidong, Chen, Xiang, Kong, Yuhan, Zhang, Jiye, Wang, Jinhua, Rogers, Mary Rose, Zhang, Hongyu, Shui, Wei, Zhao, Chen, Wang, Ning, Liang, Xi, Wu, Ningning, He, Yunfeng, Luu, Hue H., Haydon, Rex C., Shi, Lewis L., Li, Tingyu, He, Tong-Chuan, and Li, Ming

Published
2013
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19. Proteasome activity regulates CD8+ T lymphocyte metabolism and fate specification

Author

Sub Biomol.Mass Spectrometry & Proteom., Biomolecular Mass Spectrometry and Proteomics, Widjaja, Christella E., Olvera, Jocelyn G., Metz, Patrick J., Phan, Anthony T., Savas, Jeffrey N., de Bruin, Gerjan, Leestemaker, Yves, Berkers, Celia R., De Jong, Annemieke, Florea, Bogdan I., Fisch, Kathleen, Lopez, Justine, Kim, Stephanie H., Garcia, Daniel A., Searles, Stephen, Bui, Jack D., Chang, Aaron N., Yates, John R, Goldrath, Ananda W., Overkleeft, Hermen S., Ovaa, Huib, Chang, John T., Sub Biomol.Mass Spectrometry & Proteom., Biomolecular Mass Spectrometry and Proteomics, Widjaja, Christella E., Olvera, Jocelyn G., Metz, Patrick J., Phan, Anthony T., Savas, Jeffrey N., de Bruin, Gerjan, Leestemaker, Yves, Berkers, Celia R., De Jong, Annemieke, Florea, Bogdan I., Fisch, Kathleen, Lopez, Justine, Kim, Stephanie H., Garcia, Daniel A., Searles, Stephen, Bui, Jack D., Chang, Aaron N., Yates, John R, Goldrath, Ananda W., Overkleeft, Hermen S., Ovaa, Huib, and Chang, John T.

Published
2017

20. Insulin-like Growth Factor 2 (IGF-2) Potentiates BMP-9-Induced Osteogenic Differentiation and Bone Formation

Author

Chen, Liang, Jiang, Wei, Huang, Jiayi, He, Bai-Cheng, Zuo, Guo-Wei, Zhang, Wenli, Luo, Qing, Shi, Qiong, Zhang, Bing-Qiang, Wagner, Eric R, Luo, Jinyong, Tang, Min, Wietholt, Christian, Luo, Xiaoji, Bi, Yang, Su, Yuxi, Liu, Bo, Kim, Stephanie H, He, Connie J, Hu, Yawen, Shen, Jikun, Rastegar, Farbod, Huang, Enyi, Gao, Yanhong, Gao, Jian-Li, Zhou, Jian-Zhong, Reid, Russell R, Luu, Hue H, Haydon, Rex C, He, Tong-Chuan, and Deng, Zhong-Liang

Subjects
Bone Matrix, Smad Proteins, Mesenchymal Stem Cell Transplantation, Cell Line, Mice, Phosphatidylinositol 3-Kinases, Calcification, Physiologic, Chondrocytes, Fetus, Implants, Experimental, Insulin-Like Growth Factor II, Osteogenesis, Growth Differentiation Factor 2, Animals, Humans, BMP-9, bone formation, Cell Proliferation, Cell Differentiation, Mesenchymal Stem Cells, Hypertrophy, Alkaline Phosphatase, fracture healing, IGF-2, Insulin-Like Growth Factor Binding Protein 3, Insulin-Like Growth Factor Binding Protein 4, Original Article, osteoblastic differentiation, Proto-Oncogene Proteins c-akt, Biomarkers, Signal Transduction
Abstract

Efficient osteogenic differentiation and bone formation from mesenchymal stem cells (MSCs) should have clinical applications in treating nonunion fracture healing. MSCs are adherent bone marrow stromal cells that can self-renew and differentiate into osteogenic, chondrogenic, adipogenic, and myogenic lineages. We have identified bone morphogenetic protein 9 (BMP-9) as one of the most osteogenic BMPs. Here we investigate the effect of insulin-like growth factor 2 (IGF-2) on BMP-9-induced bone formation. We have found that endogenous IGF-2 expression is low in MSCs. Expression of IGF-2 can potentiate BMP-9-induced early osteogenic marker alkaline phosphatase (ALP) activity and the expression of later markers. IGF-2 has been shown to augment BMP-9-induced ectopic bone formation in the stem cell implantation assay. In perinatal limb explant culture assay, IGF-2 enhances BMP-9-induced endochondral ossification, whereas IGF-2 itself can promote the expansion of the hypertropic chondrocyte zone of the cultured limb explants. Expression of the IGF antagonists IGFBP3 and IGFBP4 leads to inhibition of the IGF-2 effect on BMP-9-induced ALP activity and matrix mineralization. Mechanistically, IGF-2 is further shown to enhance the BMP-9-induced BMPR-Smad reporter activity and Smad1/5/8 nuclear translocation. PI3-kinase (PI3K) inhibitor LY294002 abolishes the IGF-2 potentiation effect on BMP-9-mediated osteogenic signaling and can directly inhibit BMP-9 activity. These results demonstrate that BMP-9 crosstalks with IGF-2 through PI3K/AKT signaling pathway during osteogenic differentiation of MSCs. Taken together, our findings suggest that a combination of BMP-9 and IGF-2 may be explored as an effective bone-regeneration agent to treat large segmental bony defects, nonunion fracture, and/or osteoporotic fracture. © 2010 American Society for Bone and Mineral Research.

Published
2010

22. A Critical Analysis of the Role of SNARE Protein SEC22B in Antigen Cross-Presentation

Author

Wu, S. Julia, primary, Niknafs, Yashar S., additional, Kim, Stephanie H., additional, Oravecz-Wilson, Katherine, additional, Zajac, Cynthia, additional, Toubai, Tomomi, additional, Sun, Yaping, additional, Prasad, Jayendra, additional, Peltier, Daniel, additional, Fujiwara, Hideaki, additional, Hedig, Israel, additional, Mathewson, Nathan D., additional, Khoriaty, Rami, additional, Ginsburg, David, additional, and Reddy, Pavan, additional

Published
2017
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23. Early transcriptional and epigenetic regulation of CD8+ T cell differentiation revealed by single-cell RNA sequencing

Author

Kakaradov, Boyko, primary, Arsenio, Janilyn, additional, Widjaja, Christella E, additional, He, Zhaoren, additional, Aigner, Stefan, additional, Metz, Patrick J, additional, Yu, Bingfei, additional, Wehrens, Ellen J, additional, Lopez, Justine, additional, Kim, Stephanie H, additional, Zuniga, Elina I, additional, Goldrath, Ananda W, additional, Chang, John T, additional, and Yeo, Gene W, additional

Published
2017
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24. Integrin activation controls regulatory T cell identity and stability

Author

Klann, Jane Elizabeth, primary, Kim, Stephanie H, additional, Remedios, Kelly A, additional, Metz, Patrick J, additional, Snider, Adam K, additional, Lopez, Justine, additional, Cantor, Joseph M, additional, Ablack, Jai N, additional, Mack, Lauren A, additional, Zheng, Ye, additional, Lu, Li-Fan, additional, Bui, Jack D, additional, Ginsberg, Mark H, additional, Petrich, Brian G, additional, and Chang, John T, additional

Published
2016
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26. Epigenetic Regulation of Mesenchymal Stem Cells: A Focus on Osteogenic and Adipogenic Differentiation

Author

Teven, Chad M., Liu, Xing, Hu, Ning, Tang, Ni, Kim, Stephanie H., Huang, Enyi, Yang, Ke, Li, Mi, Gao, Jian-Li, Liu, Hong, Natale, Ryan B., Luther, Gaurav, Luo, Qing, Wang, Linyuan, Rames, Richard, Bi, Yang, Luo, Jinyong, Luu, Hue H., Haydon, Rex C., Reid, Russell R., and He, Tong-Chuan

Subjects
Article Subject
Abstract

Stem cells are characterized by their capability to self-renew and terminally differentiate into multiple cell types. Somatic or adult stem cells have a finite self-renewal capacity and are lineage-restricted. The use of adult stem cells for therapeutic purposes has been a topic of recent interest given the ethical considerations associated with embryonic stem (ES) cells. Mesenchymal stem cells (MSCs) are adult stem cells that can differentiate into osteogenic, adipogenic, chondrogenic, or myogenic lineages. Owing to their ease of isolation and unique characteristics, MSCs have been widely regarded as potential candidates for tissue engineering and repair. While various signaling molecules important to MSC differentiation have been identified, our complete understanding of this process is lacking. Recent investigations focused on the role of epigenetic regulation in lineage-specific differentiation of MSCs have shown that unique patterns of DNA methylation and histone modifications play an important role in the induction of MSC differentiation toward specific lineages. Nevertheless, MSC epigenetic profiles reflect a more restricted differentiation potential as compared to ES cells. Here we review the effect of epigenetic modifications on MSC multipotency and differentiation, with a focus on osteogenic and adipogenic differentiation. We also highlight clinical applications of MSC epigenetics and nuclear reprogramming.

Published
2011
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29. Molecular basis of differentiation therapy for soft tissue sarcomas

Author

Luther, Gaurav, Rames, Richard, Wagner, Eric R., Zhu, Gaohui, Luo, Qing, Bi, Yang, Kim, Stephanie H., Gao, Jian-Li, Huang, Enyi, Yang, Ke, Wang, Linyuan, Liu, Xing, Li, Mi, Hu, Ning, Su, Yuxi, Luo, Xiaoji, Chen, Liang, Luo, Jinyong, Haydon, Rex C., Luu, Hue H., Zhou, Lan, and He, Tong-Chuan

Subjects
Article
Abstract

Stem cells are undifferentiated precursor cells with the capacity for proliferation or terminal differentiation. Progression down the differentiation cascade results in a loss of proliferative potential in exchange for the differentiated phenotype. This balance is tightly regulated in the physiologic state. Recent studies, however, have demonstrated that during tumorigenesis, disruptions preventing terminal differentiation allow cancer cells to maintain a proliferative, precursor cell phenotype. Current therapies (i.e., chemotherapy and radiation therapy) target the actively proliferating cells in tumor masses, which in many cases inevitably induce therapy-resistant cancer cells. It is conceivable that promising therapy regimens can be developed by treating human cancers by inducing terminal differentiation, thereby restoring the interrupted pathway and shifting the balance from proliferation to differentiation. For example, osteosarcoma (OS) is a primary bone cancer caused by differentiation defects in mesenchymal stem cells (MSCs) for which several differentiation therapies have shown great promise. In this review, we discuss the various differentiation therapies in the treatment of human sarcomas with a focus on OS. Such therapies hold great promise as they not only inhibit tumorigenesis, but also avoid the adverse effects associated with conventional chemotherapy regimens. Furthermore, it is conceivable that a combination of conventional therapies with differentiation therapy should significantly improve anticancer efficacy and reduce drug-resistance in the clinical management of human cancers, including sarcomas.

Published
2010

30. Mesenchymal Progenitor Cells and Their Orthopedic Applications: Forging a Path towards Clinical Trials

Author

Shenaq, Deana S., Rastegar, Farbod, Petkovic, Djuro, Zhang, Bing-Qiang, He, Bai-Cheng, Chen, Liang, Zuo, Guo-Wei, Luo, Qing, Shi, Qiong, Wagner, Eric R., Huang, Enyi, Gao, Yanhong, Gao, Jian-Li, Kim, Stephanie H., Yang, Ke, Bi, Yang, Su, Yuxi, Zhu, Gaohui, Luo, Jinyong, Luo, Xiaoji, Qin, Jiaqiang, Reid, Russell R., Luu, Hue H., Haydon, Rex C., and He, Tong-Chuan

Subjects
Article Subject
Abstract

Mesenchymal progenitor cells (MPCs) are nonhematopoietic multipotent cells capable of differentiating into mesenchymal and nonmesenchymal lineages. While they can be isolated from various tissues, MPCs isolated from the bone marrow are best characterized. These cells represent a subset of bone marrow stromal cells (BMSCs) which, in addition to their differentiation potential, are critical in supporting proliferation and differentiation of hematopoietic cells. They are of clinical interest because they can be easily isolated from bone marrow aspirates and expanded in vitro with minimal donor site morbidity. The BMSCs are also capable of altering disease pathophysiology by secreting modulating factors in a paracrine manner. Thus, engineering such cells to maximize therapeutic potential has been the focus of cell/gene therapy to date. Here, we discuss the path towards the development of clinical trials utilizing BMSCs for orthopaedic applications. Specifically, we will review the use of BMSCs in repairing critical-sized defects, fracture nonunions, cartilage and tendon injuries, as well as in metabolic bone diseases and osteonecrosis. A review of www.ClinicalTrials.gov of the United States National Institute of Health was performed, and ongoing clinical trials will be discussed in addition to the sentinel preclinical studies that paved the way for human investigations.

Published
2010
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31. The CCN proteins: important signaling mediators in stem cell differentiation and tumorigenesis

Author

Zuo, Guo-Wei, Kohls, Christopher D., He, Bai-Cheng, Chen, Liang, Zhang, Wenli, Shi, Qiong, Zhang, Bing-Qiang, Kang, Quan, Luo, Jinyong, Luo, Xiaoji, Wagner, Eric R., Kim, Stephanie H., Restegar, Farbod, Haydon, Rex C., Deng, Zhong-Liang, Luu, Hue H., He, Tong-Chuan, and Luo, Qing

Subjects
Stem cell, Tumorigenesis, 61 - Medicina
Abstract

The CCN proteins contain six members, namely CCN1 to CCN6, which are small secreted cysteine-rich proteins. The CCN proteins are modular proteins, containing up to four functional domains. Many of the CCN members are induced by growth factors, cytokines, or cellular stress. The CCNs show a wide and highly variable expression pattern in adult and in embryonic tissues. The CCN proteins can integrate and modulate the signals of integrins, BMPs, VEGF, Wnts, and Notch. The involvement of integrins in mediating CCN signaling may provide diverse contextdependent responses in distinct cell types. CCN1 and CCN2 play an important role in development, angiogenesis and cell adhesion, whereas CCN3 is critical to skeletal and cardiac development. CCN4, CCN5 and CCN6 usually inhibit cell growth. Mutations of Ccn6 are associated with the progressive pseudorheumatoid dysplasia and spondyloepiphyseal dysplasia tarda. In stem cell differentiation, CCN1, CCN2, and CCN3 play a principal role in osteogenesis, chondrogenesis, and angiogenesis. Elevated expression of CCN1 is associated with more aggressive phenotypes of human cancer, while the roles of CCN2 and CCN3 in tumorigenesis are tumor type-dependent. CCN4, CCN5 and CCN6 function as tumor suppressors. Although CCN proteins may play important roles in fine-tuning other major signaling pathways, the precise function and mechanism of action of these proteins remain undefined. Understanding of the biological functions of the CCN proteins would not only provide insight into their roles in numerous cellular processes but also offer opportunities for developing therapeutics by targeting CCN functions.

Published
2010

32. 716 Immunodeficiency and Autoimmune Enterocolopathy Linked to NFAT5 Deficiency

Author

Boland, Brigid S., primary, Widjaja, Christella E., additional, Banno, Asoka, additional, Kim, Stephanie H., additional, Peterson, Michael R., additional, Jones, Marilyn C., additional, Su, H.I., additional, Crowe, Sheila E., additional, Bui, Jack, additional, Aramburu, Jose F., additional, Lopez-Rodriguez, Cristina, additional, Sandborn, William, additional, and Chang, John T., additional

Published
2014
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34. Endoplasmic Reticulum (ER) Stress Inducible Factor Cysteine-Rich with EGF-Like Domains 2 (Creld2) Is an Important Mediator of BMP9-Regulated Osteogenic Differentiation of Mesenchymal Stem Cells

Author

Zhang, Jiye, primary, Weng, Yaguang, additional, Liu, Xing, additional, Wang, Jinhua, additional, Zhang, Wenwen, additional, Kim, Stephanie H., additional, Zhang, Hongyu, additional, Li, Ruidong, additional, Kong, Yuhan, additional, Chen, Xiang, additional, Shui, Wei, additional, Wang, Ning, additional, Zhao, Chen, additional, Wu, Ningning, additional, He, Yunfeng, additional, Nan, Guoxin, additional, Chen, Xian, additional, Wen, Sheng, additional, Zhang, Hongmei, additional, Deng, Fang, additional, Wan, Lihua, additional, Luu, Hue H., additional, Haydon, Rex C., additional, Shi, Lewis L., additional, He, Tong-Chuan, additional, and Shi, Qiong, additional

Published
2013
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35. Wnt signaling in bone formation and its therapeutic potential for bone diseases

Author

Kim, Jeong Hwan, primary, Liu, Xing, additional, Wang, Jinhua, additional, Chen, Xiang, additional, Zhang, Hongyu, additional, Kim, Stephanie H., additional, Cui, Jing, additional, Li, Ruidong, additional, Zhang, Wenwen, additional, Kong, Yuhan, additional, Zhang, Jiye, additional, Shui, Wei, additional, Lamplot, Joseph, additional, Rogers, Mary Rose, additional, Zhao, Chen, additional, Wang, Ning, additional, Rajan, Prashant, additional, Tomal, Justin, additional, Statz, Joseph, additional, Wu, Ningning, additional, Luu, Hue H., additional, Haydon, Rex C., additional, and He, Tong-Chuan, additional

Published
2013
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36. Correction: Conditionally Immortalized Mouse Embryonic Fibroblasts Retain Proliferative Activity without Compromising Multipotent Differentiation Potential

Author

Huang, Enyi, primary, Bi, Yang, additional, Jiang, Wei, additional, Luo, Xiaoji, additional, Yang, Ke, additional, Gao, Jian-Li, additional, Gao, Yanhong, additional, Luo, Qing, additional, Shi, Qiong, additional, Kim, Stephanie H., additional, Liu, Xing, additional, Li, Mi, additional, Hu, Ning, additional, Liu, Hong, additional, Cui, Jing, additional, Zhang, Wenwen, additional, Li, Ruidong, additional, Chen, Xiang, additional, Shen, Jikun, additional, Kong, Yuhan, additional, Zhang, Jiye, additional, Wang, Jinhua, additional, Luo, Jinyong, additional, He, Bai-Cheng, additional, Wang, Huicong, additional, Reid, Russell R., additional, Luu, Hue H., additional, Haydon, Rex C., additional, Yang, Li, additional, and He, Tong-Chuan, additional

Published
2013
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37. BMP9-regulated angiogenic signaling plays an important role in the osteogenic differentiation of mesenchymal progenitor cells

Author

Hu, Ning, primary, Jiang, Dianming, additional, Huang, Enyi, additional, Liu, Xing, additional, Li, Ruidong, additional, Liang, Xi, additional, Kim, Stephanie H., additional, Chen, Xiang, additional, Gao, Jian-Li, additional, Zhang, Hongyu, additional, Zhang, Wenwen, additional, Kong, Yu-Han, additional, Zhang, Jiye, additional, Wang, Jinhua, additional, Shui, Wei, additional, Luo, Xiaoji, additional, Liu, Bo, additional, Cui, Jing, additional, Rogers, Mary Rose, additional, Shen, Jikun, additional, Zhao, Chen, additional, Wang, Ning, additional, Wu, Ningning, additional, Luu, Hue H., additional, Haydon, Rex C., additional, He, Tong-Chuan, additional, and Huang, Wei, additional

Published
2013
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38. BMP signaling in mesenchymal stem cell differentiation and bone formation

Author

Beederman, Maureen, primary, Lamplot, Joseph D., additional, Nan, Guoxin, additional, Wang, Jinhua, additional, Liu, Xing, additional, Yin, Liangjun, additional, Li, Ruidong, additional, Shui, Wei, additional, Zhang, Hongyu, additional, Kim, Stephanie H., additional, Zhang, Wenwen, additional, Zhang, Jiye, additional, Kong, Yuhan, additional, Denduluri, Sahitya, additional, Rogers, Mary Rose, additional, Pratt, Abdullah, additional, Haydon, Rex C., additional, Luu, Hue H., additional, Angeles, Jovito, additional, Shi, Lewis L., additional, and He, Tong-Chuan, additional

Published
2013
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39. Brain gym offers mental exercise

Author

Kim, Stephanie H.

Subjects
Nursing homes, Business, Health, Health care industry, Seniors, University of Florida
Abstract

Nursing home residents and surrounding community members can break a mental sweat at The Village's new brain gym offered by the University of Florida's Health Vitality Mind research program. The [...]

Published
2014

40. Study: IV feeding guidelines need revision

Author

Kim, Stephanie H.

Subjects
Glucose metabolism, Business, Health, Health care industry, Seniors
Abstract

Current guidelines for intravenous feeding may need revisions to prevent bloodstream infections more effectively, a new study suggests. Researchers from the United Kingdom's University of Southampton discovered that laboratory studies [...]

Published
2014

41. 1 in 3 knee surgeries in the U.S. may be 'inappropriate'

Author

Kim, Stephanie H.

Subjects
Surgery, Business, Health, Health care industry, Seniors
Abstract

Nearly one-third of knee replacement surgeries in the U.S. may be classified as 'inappropriate,' Virginia researchers found in a new study. Daniel L. Riddle, Ph.D., PT, and colleagues from the [...]

Published
2014

42. Nursing home refused to let worker wear hijab, EEOC says

Author

Kim, Stephanie H.

Subjects
United States. Equal Employment Opportunity Commission, Discrimination in medical care, Employment discrimination, Hijab (Custom), Costume, Islamic, Nursing homes, Business, Health, Health care industry, Seniors
Abstract

An Alabama nursing home faces a lawsuit for allegedly refusing to allow a Muslim employee to wear a hijab. The U.S. Equal Employment Opportunity Commission filed a workplace discrimination lawsuit [...]

Published
2014

43. Most residents are incontinent

Author

Kim, Stephanie H.

Subjects
Residents (Medicine) -- Health aspects -- Care and treatment, Urinary incontinence -- Demographic aspects -- Care and treatment, Business, Health, Health care industry, Seniors
Abstract

More than 75% of long-term residents are incontinent, as well as nearly half (46%) of short-term residents, the Centers for Disease Control and Prevention reported. Residents who couldn't control their [...]

Published
2014

44. Tool gives providers a leg up when assessing malnutrition

Author

Kim, Stephanie H.

Subjects
Malnutrition, Nursing homes, Business, Health, Health care industry, Seniors
Abstract

The calf circumference of residents is a 'good substitute' for body mass index when using the Mini Nutritional Assessment Short-Form, according to a study published in May. 'MNA is an [...]

Published
2014

45. Study takes a closer look at falling risks

Author

Kim, Stephanie H.

Subjects
Falls (Accidents) -- Risk factors, Aged -- Health aspects -- Accidents, Business, Health, Health care industry, Seniors
Abstract

While it is clear that poor vision increases the risk of falling, improved vision might also increase this risk, a new study suggests. David Elliot, Ph.D., professor of clinical vision [...]

Published
2014

46. $11.6m to nurse paralyzed by flu vaccine

Author

Kim, Stephanie H.

Subjects
Guillain-Barre syndrome, Influenza vaccines, Influenza, Nurses, Nursing homes, Business, Health, Health care industry, Seniors
Abstract

A former nurse has received an $11.6 million government settlement to pay for future care after a flu vaccine paralyzed her. Sarah Behie, 24, received the flu vaccine in October [...]

Published
2014

47. Certain lights ease dementia

Author

Kim, Stephanie H.

Subjects
Dementia, Business, Health, Health care industry, Seniors
Abstract

Certain lights may improve quality of life for residents with Alzheimer's and other types of dementia, according to a new study. Blue-white lights were installed in 14 rooms of residents [...]

Published
2014

48. Special juice reduces UTIs

Author

Kim, Stephanie H.

Subjects
Urinary tract infections, Fruit juices, Nursing homes, Business, Health, Health care industry, Seniors
Abstract

Drinking black chokeberry juice may reduce the rate of urinary tract infections among nursing home residents, according to findings published in Nutrition Research in June. About 200 residents from six [...]

Published
2014

49. Conditional Immortalization Establishes a Repertoire of Mouse Melanocyte Progenitors with Distinct Melanogenic Differentiation Potential

Author

Yang, Ke, primary, Chen, Jin, additional, Jiang, Wei, additional, Huang, Enyi, additional, Cui, Jing, additional, Kim, Stephanie H., additional, Hu, Ning, additional, Liu, Hong, additional, Zhang, Wenwen, additional, Li, Ruidong, additional, Chen, Xiang, additional, Kong, Yuhan, additional, Zhang, Jiye, additional, Wang, Jinhua, additional, Wang, Linyuan, additional, Shen, Jikun, additional, Luu, Hue H., additional, Haydon, Rex C., additional, Lian, Xiaohua, additional, Yang, Tian, additional, and He, Tong-Chuan, additional

Published
2012
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50. Growth hormone synergizes with BMP9 in osteogenic differentiation by activating the JAK/STAT/IGF1 pathway in murine multilineage cells

Author

Huang, Enyi, primary, Zhu, Gaohui, additional, Jiang, Wei, additional, Yang, Ke, additional, Gao, Yanhong, additional, Luo, Qing, additional, Gao, Jian-Li, additional, Kim, Stephanie H, additional, Liu, Xing, additional, Li, Mi, additional, Shi, Qiong, additional, Hu, Ning, additional, Wang, Linyuan, additional, Liu, Hong, additional, Cui, Jing, additional, Zhang, Wenwen, additional, Li, Ruidong, additional, Chen, Xiang, additional, Kong, Yu-Han, additional, Zhang, Jiye, additional, Wang, Jinhua, additional, Shen, Jikun, additional, Bi, Yang, additional, Statz, Joseph, additional, He, Bai-Cheng, additional, Luo, Jinyong, additional, Wang, Huicong, additional, Xiong, Feng, additional, Luu, Hue H, additional, Haydon, Rex C, additional, Yang, Li, additional, and He, Tong-Chuan, additional

Published
2012
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