Bio

Honors & Awards


  • National Merit Scholarship, National Merit Scholarship (1999-2003)
  • Graduate Fellowship in Biomedical Engineering, Whitaker Foundation (2003-2006)
  • Benjamin Trump Award and Fellowship, Aspen Cancer Conference (2008)
  • Graduate Research Award, Biomedical Engineering Society (BMES) (2008)
  • Stanford Molecular Imaging Scholars (SMIS) Postdoctoral Fellowship, Molecular Imaging Program at Stanford (2009-2012)
  • K99/R00 Pathway to Independence Award, NIH/NIA (2012-2017)

Professional Education


  • B.Bm.E., University of Minnesota, Biomedical Engineering (2003)
  • Doctor of Philosophy, Massachusetts Institute of Technology (2009)

Stanford Advisors


Research & Scholarship

Lab Affiliations


  • Helen Blau, Baxter Laboratory for Stem Cell Biology (1/5/2009)

Publications

Journal Articles


  • Rejuvenation of the muscle stem cell population restores strength to injured aged muscles. Nature medicine Cosgrove, B. D., Gilbert, P. M., Porpiglia, E., Mourkioti, F., Lee, S. P., Corbel, S. Y., Llewellyn, M. E., Delp, S. L., Blau, H. M. 2014; 20 (3): 255-264

    Abstract

    The elderly often suffer from progressive muscle weakness and regenerative failure. We demonstrate that muscle regeneration is impaired with aging owing in part to a cell-autonomous functional decline in skeletal muscle stem cells (MuSCs). Two-thirds of MuSCs from aged mice are intrinsically defective relative to MuSCs from young mice, with reduced capacity to repair myofibers and repopulate the stem cell reservoir in vivo following transplantation. This deficiency is correlated with a higher incidence of cells that express senescence markers and is due to elevated activity of the p38? and p38? mitogen-activated kinase pathway. We show that these limitations cannot be overcome by transplantation into the microenvironment of young recipient muscles. In contrast, subjecting the MuSC population from aged mice to transient inhibition of p38? and p38? in conjunction with culture on soft hydrogel substrates rapidly expands the residual functional MuSC population from aged mice, rejuvenating its potential for regeneration and serial transplantation as well as strengthening of damaged muscles of aged mice. These findings reveal a synergy between biophysical and biochemical cues that provides a paradigm for a localized autologous muscle stem cell therapy for the elderly.

    View details for DOI 10.1038/nm.3464

    View details for PubMedID 24531378

  • Cytokine-associated drug toxicity in human hepatocytes is associated with signaling network dysregulation MOLECULAR BIOSYSTEMS Cosgrove, B. D., Alexopoulos, L. G., Hang, T., Hendriks, B. S., Sorger, P. K., Griffith, L. G., Lauffenburger, D. A. 2010; 6 (7): 1195-1206

    Abstract

    Idiosyncratic drug hepatotoxicity is a major problem in pharmaceutical development due to poor prediction capability of standard preclinical toxicity assessments and limited knowledge of its underlying mechanisms. Findings in animal models have shown that adverse effects of numerous drugs with idiosyncratic hepatotoxicity in humans can be reproduced in the presence of coincident inflammatory cytokine signaling. Following these observations, we have recently developed an in vitro drug/inflammatory cytokine co-treatment approach that can reproduce clinical drug hepatotoxicity signatures-particularly for idiosyncratic drugs-in cultured primary human hepatocytes. These observations have suggested that drug-induced stresses may interact with cytokine signaling to induce hepatic cytotoxicity, but the hepatocyte signaling mechanisms governing these interactions are poorly understood. Here, we collect high-throughput phosphoprotein signaling and cytotoxicity measurements in cultured hepatocytes, from multiple human donors, treated with combinations of hepatotoxic drugs (e.g. trovafloxacin, clarithromycin) and cytokines (tumor necrosis factor-alpha, interferon-gamma, interleukin-1 alpha, and interleukin-6). We demonstrate, through orthogonal partial least-squares regression (OPLSR) modeling of these signal-response data, that drug/cytokine hepatic cytotoxicity is integratively controlled by four key signaling pathways: Akt, p70 S6 kinase, MEK-ERK, and p38-HSP27. This modeling predicted, and experimental studies confirmed, that the MEK-ERK and p38-HSP27 pathways contribute pro-death signaling influences in drug/cytokine hepatic cytotoxicity synergy. Further, our four-pathway OPLSR model produced successful prediction of drug/cytokine hepatic cytotoxicities across different human donors, even though signaling and cytotoxicity responses were both highly donor-specific. Our findings highlight the critical role of kinase signaling in drug/cytokine hepatic cytotoxicity synergies and reveal that hepatic cytotoxicity responses are governed by multi-pathway signaling network balance.

    View details for DOI 10.1039/b926287c

    View details for Web of Science ID 000278861500009

    View details for PubMedID 20361094

  • A home away from home: Challenges and opportunities in engineering in vitro muscle satellite cell niches DIFFERENTIATION Cosgrove, B. D., Sacco, A., Gilbert, P. M., Blau, H. M. 2009; 78 (2-3): 185-194

    Abstract

    Satellite cells are skeletal muscle stem cells with a principal role in postnatal skeletal muscle regeneration. Satellite cells, like many tissue-specific adult stem cells, reside in a quiescent state in an instructive, anatomically defined niche. The satellite cell niche constitutes a distinct membrane-enclosed compartment within the muscle fiber, containing a diversity of biochemical and biophysical signals that influence satellite cell function. A major limitation to the study and clinical utility of satellite cells is that upon removal from the muscle fiber and plating in traditional plastic tissue culture platforms, their muscle stem cell properties are rapidly lost. Clearly, the maintenance of stem cell function is critically dependent on in vivo niche signals, highlighting the need to create novel in vitro microenvironments that allow for the maintenance and propagation of satellite cells while retaining their potential to function as muscle stem cells. Here, we discuss how emerging biomaterials technologies offer great promise for engineering in vitro microenvironments to meet these challenges. In engineered biomaterials, signaling molecules can be presented in a manner that more closely mimics cell-cell and cell-matrix interactions, and matrices can be fabricated with diverse rigidities that approximate in vivo tissues. The development of in vitro microenvironments in which niche features can be systematically modulated will be instrumental not only to future insights into muscle stem cell biology and therapeutic approaches to muscle diseases and muscle wasting with aging, but also will provide a paradigm for the analysis of numerous adult tissue-specific stem cells.

    View details for DOI 10.1016/j.diff.2009.08.004

    View details for Web of Science ID 000274532300017

    View details for PubMedID 19751902

  • Microfluidic Concentration-Enhanced Cellular Kinase Activity Assay JOURNAL OF THE AMERICAN CHEMICAL SOCIETY Lee, J. H., Cosgrove, B. D., Lauffenburger, D. A., Han, J. 2009; 131 (30): 10340-?

    Abstract

    In this paper, we reported a simple, disposable PDMS micro/nanofluidic preconcentration chip for in vitro concentration-enhanced cell kinase assays. Utilizing the preconcentration (electrokinetic trapping) directly from cell lysate (1 mM ATP) samples, we could achieve at least a 25-fold increase in reaction velocity and 65-fold enhancement in sensitivity. In addition, we shorten the assay time down to less than 10 min, with the sample volume requirements of down to approximately 5 cells. This device could be a generic and powerful tool for diagnostics and systems biology studies at the single-cell level, if properly optimized and integrated with the cell culture microdevices.

    View details for DOI 10.1021/ja902594f

    View details for Web of Science ID 000268644400003

    View details for PubMedID 19722608

  • Three-kinase inhibitor combination recreates multipathway effects of a geldanamycin analogue on hepatocellular carcinoma cell death MOLECULAR CANCER THERAPEUTICS Pritchard, J. R., Cosgrove, B. D., Hemann, M. T., Griffith, L. G., Wands, J. R., Lauffenburger, D. A. 2009; 8 (8): 2183-2192

    Abstract

    Multitarget compounds that act on a diverse set of regulatory pathways are emerging as a therapeutic approach for a variety of cancers. Toward a more specified use of this approach, we hypothesize that the desired efficacy can be recreated in terms of a particular combination of relatively more specific (i.e., ostensibly single target) compounds. We test this hypothesis for the geldanamycin analogue 17-Allylamino-17-demethoxygeldanamycin (17AAG) in hepatocellular carcinoma cells, measuring critical phosphorylation levels that indicate the kinase pathway effects correlating with apoptotic responsiveness of the Hep3B cell line in contrast to the apoptotic resistance of the Huh7 cell line. A principal components analysis (PCA) constructed from time course measurements of seven phosphoprotein signaling levels identified modulation of the AKT, IkappaB kinase, and signal transducer and activator of transcription 3 pathways by 17AAG treatment as most important for distinguishing these cell-specific death responses. The analysis correctly suggested from 17AAG-induced effects on these phosphoprotein levels that the FOCUS cell line would show apoptotic responsiveness similarly to Hep3B. The PCA also guided the inhibition of three critical pathways and rendered Huh7 cells responsive to 17AAG. Strikingly, in all three hepatocellular carcinoma lines, the three-inhibitor combination alone exhibited similar or greater efficacy to 17AAG. We conclude that (a) the PCA captures and clusters the multipathway phosphoprotein time courses with respect to their 17AAG-induced apoptotic responsiveness and (b) we can recreate, in a more specified manner, the cellular responses of a prospective multitarget cancer therapeutic.

    View details for DOI 10.1158/1535-7163.MCT-08-1203

    View details for Web of Science ID 000269029300013

    View details for PubMedID 19671754

  • Synergistic drug-cytokine induction of hepatocellular death as an in vitro approach for the study of inflammation-associated idiosyncratic drug hepatotoxicity TOXICOLOGY AND APPLIED PHARMACOLOGY Cosgrove, B. D., King, B. M., Hasan, M. A., Alexopoulos, L. G., Farazi, P. A., Hendriks, B. S., Griffith, L. G., Sorger, P. K., Tidor, B., Xu, J. J., Lauffenburger, D. A. 2009; 237 (3): 317-330

    Abstract

    Idiosyncratic drug hepatotoxicity represents a major problem in drug development due to inadequacy of current preclinical screening assays, but recently established rodent models utilizing bacterial LPS co-administration to induce an inflammatory background have successfully reproduced idiosyncratic hepatotoxicity signatures for certain drugs. However, the low-throughput nature of these models renders them problematic for employment as preclinical screening assays. Here, we present an analogous, but high-throughput, in vitro approach in which drugs are administered to a variety of cell types (primary human and rat hepatocytes and the human HepG2 cell line) across a landscape of inflammatory contexts containing LPS and cytokines TNF, IFN gamma, IL-1 alpha, and IL-6. Using this assay, we observed drug-cytokine hepatotoxicity synergies for multiple idiosyncratic hepatotoxicants (ranitidine, trovafloxacin, nefazodone, nimesulide, clarithromycin, and telithromycin) but not for their corresponding non-toxic control compounds (famotidine, levofloxacin, buspirone, and aspirin). A larger compendium of drug-cytokine mix hepatotoxicity data demonstrated that hepatotoxicity synergies were largely potentiated by TNF, IL-1 alpha, and LPS within the context of multi-cytokine mixes. Then, we screened 90 drugs for cytokine synergy in human hepatocytes and found that a significantly larger fraction of the idiosyncratic hepatotoxicants (19%) synergized with a single cytokine mix than did the non-hepatotoxic drugs (3%). Finally, we used an information theoretic approach to ascertain especially informative subsets of cytokine treatments for most highly effective construction of regression models for drug- and cytokine mix-induced hepatotoxicities across these cell systems. Our results suggest that this drug-cytokine co-treatment approach could provide a useful preclinical tool for investigating inflammation-associated idiosyncratic drug hepatotoxicity.

    View details for DOI 10.1016/j.taap.2009.04.002

    View details for Web of Science ID 000266689800008

    View details for PubMedID 19362101

  • An inducible autocrine cascade regulates rat hepatocyte proliferation and apoptosis responses to tumor necrosis factor-alpha HEPATOLOGY Cosgrove, B. D., Cheng, C., Pritchard, J. R., Stolz, D. B., Lauffenburger, D. A., Griffith, L. G. 2008; 48 (1): 276-288

    Abstract

    Tumor necrosis factor-alpha (TNF) is an inflammatory cytokine that induces context-dependent proliferation, survival, and apoptosis responses in hepatocytes. TNF stimulates and enhances growth factor-mediated hepatocyte proliferation and survival following partial hepatectomy, but also acts in concert with other inflammatory cytokines of the innate immune response during viral infection to induce apoptosis in hepatocytes. In other epithelial cell types, TNF has recently been shown to stimulate autocrine release of transforming growth factor-alpha (TGF-alpha) and interleukin-1 (IL-1) family ligands. Here, we examine the role of these autocrine ligands in modulating TNF-induced proliferation and apoptosis in primary hepatocytes. We show that TNF-induced hepatocyte proliferation is regulated by an inducible, coupled, and self-antagonizing autocrine cascade involving the pro-proliferative TGF-alpha and IL-1 receptor antagonist (IL-1ra) ligands and antiproliferative IL-1alpha/beta ligands. Moreover, cooperative stimulation of hepatocyte proliferation by combined TNF and TGF-alpha treatment is self-limited through antiproliferative autocrine IL-1alpha/beta feedback. We show that TNF potently induces apoptosis of adenovirus-infected hepatocytes in a manner similarly determined through the integrated activity of a coupled TGF-alpha-IL-1alpha/beta-IL-1ra autocrine cascade. Exogenous TGF-alpha can either enhance or diminish apoptosis in adenoviral vector-treated and TNF-treated hepatocytes, in a biphasic relationship also mediated by autocrine IL-1alpha/beta feedback.We demonstrate that TNF-induced hepatocyte proliferation and apoptosis are both governed by a self-antagonizing TGF-alpha-IL-1alpha/beta-IL-1ra autocrine cascade in vitro, and thus identify multiple molecular targets for control of TNF-regulated hepatocyte phenotypic responses related to liver regeneration and adenoviral gene therapy.

    View details for DOI 10.1002/hep.22335

    View details for Web of Science ID 000257301100032

    View details for PubMedID 18536058

Conference Proceedings


  • A multipathway phosphoproteomic signaling network model of idiosyncratic drug- and inflammatory cytokine-induced toxicity in human hepatocytes Cosgrove, B. D., Alexopoulos, L. G., Saez-Rodriguez, J., Griffith, L. G., Lauffenburger, D. A. IEEE. 2009: 5452-5455

    Abstract

    Idiosyncratic drug hepatotoxicity is a hepatotoxicity subset that occurs in a very small fraction of human patients, is poorly predicted by standard preclinical models and in clinical trials, and frequently leads to postapproval drug failure. Animal models utilizing bacterial LPS co-administration to induce an inflammatory background and hepatocyte cell culture models utilizing cytokine mix cotreatment have successfully reproduced idiosyncratic hepatotoxicity signatures for certain drugs, but the hepatocyte signaling mechanisms governing these drug-cytokine toxicity synergizes are largely unclear. Here, we summarize our efforts to computationally model the signaling mechanisms regulating inflammatory cytokine-associated idiosyncratic drug hepatotoxicity. We collected a "cue-signal-response" (CSR) data compendium in cultured primary human hepatocytes treated with many combinations of idiosyncratic hepatotoxic drugs and inflammatory cytokine mixes ("cues") and subjected this compendium to orthogonal partial-least squares regression (OPLSR) to computationally relate the measured intracellular phosphoprotein signals and hepatocellular death responses. This OPLSR model suggested that hepatocytes specify their cell death responses to toxic drug/cytokine conditions by integrating signals from four key pathways - Akt, p70 S6K, ERK, and p38. An OPLSR model focused on data from these four signaling pathways demonstrated accurate predictions of idiosyncratic drug- and cytokine-induced hepatotoxicities in a second human hepatocyte donor, suggesting that hepatocytes from different individuals have shared network control mechanisms governing toxicity responses to diverse combinations of idiosyncratic hepatotoxicants and inflammatory cytokines.

    View details for Web of Science ID 000280543604090

    View details for PubMedID 19964679

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