The Humphreys Lab
The mission of the Humphreys Lab is to understand the cellular and molecular mechanisms of kidney repair and thereby identify new therapeutic strategies for humans suffering from kidney disease. The work encompasses two main areas: (1) Developing stem cell-based approaches to treat kidney disease in humans and (2) understanding the mechanisms of kidney repair and recovery after injury. www.twitter.com/HumphreysLab
Humphreys Lab News
March, 2014: Translational profiles of four critical cell types in acute kidney injury, just published in JCI. A comprehensive resource to identify new biomarkers and therapeutic targets, and a powerful technique for isolation of cell-specific RNA.
February, 2014: "Pharmacologic Quiescence" is a new strategy to protect against Acute Kidney Injury - our new paper was selected as an Editor's Pick. This work is first to implicate CDK4/6 as critical proliferative switch in proximal tubule epithelia, and suggests a novel therapeutic strategy.
November, 2013: A molecular mechanism to help explain the epidemiological link between AKI and risk of future CKD/kidney failure, according to our work published in JCI.
October, 2013: Our new article in PNAS uses lineage tracing of differentiated cells to define how injured tubules repair.
September, 2013: A very successful Stem Cells and Kidney Regeneration ISN Forefronts meeting was held in Florence, Italy September 12-15, chaired by Paola Romagnani and Ben Humphreys.
May, 2013:Congratulations MatriTarg Laboratories for winning the 2013 Dean's Health and Life Sciences Challenge!
May, 2013:Congratulations Hitesh for being accepted to graduate school!
Congratulations to Mari for receiving Honors on her Senior Thesis for the Harvard Department of Stem Cell and Regenerative Biology!
April, 2013: Continuing on their recent successes, an effort headed by Derek DiRocco, PhD and with Rafael Kramann, MD, was chosen from a Harvard-wide competition as finalists in the 2013 Dean's Health and Life Sciences Challenge, for their application "MatriTarg Laboratories" aimed at discovering innovative new treatments for solid organ fibrosis. See the announcement in the Harvard Gazette and the BWH Website
March, 2013: Derek DiRocco, PhD and Rafael Kramann, MD, were each winners in the HSCI Image Contest!
January, 2013: Omar Maarouf, MD receives BWH Department of Medicine Renal Fellow of the year. Congratulations Omar!
January, 2013: Ben Humphreys, MD, PhD receives American Heart Association Established Investigator Award.
December, 2012: Radostin Penchev is accepted to medical school. Congratulations!
November, 2012: Ivica Grgic, MD wins "Top Oral Abstract by a Trainee" at American Society of Nephrology National Meeting for his oral presentation, "New Genetic Tool for the Study of Pericytes and Perivascular Fibroblasts."
October, 2012: HSCI Kidney Program Retreat The HSCI Kidney Program hosted a very successful retreat featuring local speakers plus visiting scholars Lloyd Cantley, MD (Yale) and HSCI Distinguished Speaker Melissa Little, PhD (University of Queensland).
May, 2012: Humphreys Lab wins FASEB 2012 Bio-Art Competition for visualizing podocyte foot process by fluorescence microscopy. The competition sought "captivating, high resolution images that represent the cutting edge of 21st century biomedical research."
Genetic Analysis of Kidney Injury and Repair
Lineage tracing during renal repair. A major current focus of the lab is to investigate the lineage relationships among cell types during renal repair to assess whether adult stem cells contribute to repair. We have developed a method for distinguishing between renal repair by extratubular progenitor cells and renal epithelial cells. We have used a transgenic mouse in which the Six2 promoter drives Cre recombinase in collaboration with the Bonventre and McMahon groups at Harvard. In this strain, Cre is expressed transiently in renal epithelial precursors during development, with no Cre expression in the adult or re-expression after injury. We crossed this Six2-Cre mouse with a reporter strain in which Cre-dependent removal of a stop sequence causes constitutive and heritable expression of a marker gene such as alkaline phosphatase or DsRed. In these mice, renal epithelial cells, from Bowman’s capsule to the distal convoluted tubule, are heritably labeled but extratubular cells such as interstitial cells, remain unlabeled. To test whether unlabeled cells could contribute to the epithelial lineage during renal repair, we perform injury experiments and allow kidneys to recover. By examining repaired tubules for dilution of label vs. retention of label, we are able to assess whether any unlabeled cells contribute to repair of damaged nephrons.
High Resolution Kidney Imaging
Podocyte Foot Process Visualization by Fluorescence Microscopy. Our laboratory has deep expertise with in vivo reporter alleles and currently we are taking advantage of the strong epifluorescent signal some of these fluorophores provide to generate high resolution subcellular images. For example, this picture shows podocyte foot processes imaged for the first time using fluorescence microscopy in a study led by postdoctoral fellow Ivica Grgic, MD. Sporadic tdTomato reporter activation within the podocyte population allowed visualization down to the tertiary foot process level because the neighboring podocytes did not express tdTomato, enhancing the optical contrast between labeled and unlabeled foot processes. This technical advance should allow new approaches to understand podocyte morphogenesis and differentiation in devlopment, tracing of putative podocyte progenitor populations and the subcellular analysis of podocyte foot process proteins. Grgic et al., JASN 2012, in press.
Multipotent Intratubular Stem Cells
Telomerase expression in kidney. In other studies, we have characterized Telomerase expression in the kidney using transgenic reporters with D. Breault, CHB, to investigate whether these might mark stem cells. Our analysis indicates that a heterogeneous population of cells, nearly all in the renal papilla, express telomerase, but none of them have stem or progenitor characteristics.
- I. Grgic, A.M. Krautzberger, A. Hofmeister, M. Lalli, D.P. DiRocco, S.V. Fleig, J. Liu, J.S. Duffield, A.P. McMahon, B. Aronow and B.D. Humphreys. Translational profiles of medullary myofibroblasts during kidney fibrosis. J Am Soc Nephrol, 2014, in press.
- D. DiRocco, J. Bisi, P. Roberts, J. Strum, K. Wong, N. Sharpless and B.D. Humphreys. CDK4/6 inhibition induces epithelial cell cycle arrest and ameliorates acute kidney injury. American Journal of Physiology, Renal Physiology, 306(4):F379-88, 2014.
- T. Kusaba, M. Lalli, R. Kramann, A. Kobayashi and B.D. Humphreys. Differentiated kidney epithelial cells repair injured proximal tubule. Proc Nat Acad Sci, 111(4):1527-32, 2014.
- B.D. Humphreys. Kidney Structures Differentiated from Stem Cells. Nature Cell Biology. 2013;16(1):19-21.
- R. Kramann, D.P. DiRocco and B.D. Humphreys. Understanding the origin, activation and regulation of matrix-producing myofibroblasts for treatment of fibrotic disease. Journal of Pathology, 231(3):273-89, 2013.
- B.D. Humphreys and D.P. DiRocco. Lineage Tracing Methods and the Kidney. Kidney International, Epub.
- B.D. Humphreys, F. Xu, V. Sabbisetti, I. Grgic, S.M. Naini, N. Wang, G. Chen, S. Xiao, D. Patel, J.M. Henderson, T. Ichimura, S. Mou, S. Soeung, A.P. McMahon and J.V. Bonventre. Chronic epithelial kidney injury molecule-1 expression in mice causes inflammation, fibrosis and kidney failure. Journal of Clinical Investigation, 123(9):4023-35, 2013. Link to MS
- D. DiRocco, A. Kobayashi, M.M. Taketo, A.P. McMahon and B.D. Humphreys. Wnt4/β-catenin signaling in medullary kidney myofibroblasts. Journal of the American Society of Nephrology, 24(9):1399-412, 2013. Link to MS
- I. Grgic, C.R. Brooks, A.F. Hofmeister, V. Bijol, J.V. Bonventre and B.D. Humphreys. Podocyte foot process imaging in mouse by fluorescence microscopy. Journal of the American Society of Nephrology, 2012. Cover Art. Link to MS
- S.L. Fabian, R.R. Penchev, B. St.-Jacques, A.L. Rao, P. Sipila, A.P. McMahon and B.D. Humphreys. Hedgehog-Gli Pathway Activation During Kidney Fibrosis. American Journal of Pathology, 180(4):1441-53, 2012. Link to MS
- S. Balasubramanian, M. Jansen, M.T. Valerius, B.D. Humphreys* and Terry B. Strom.* Orphan nuclear receptor Nur77 promotes acute kidney injury and renal epithelial apoptosis in mice. Journal of the American Society of Nephrology, 23(4):674-86, 2012. *Co-senior authors. Link to MS
- J. Song, S.C. Czerniak, T. Wang, W. Ying, D.L. Carlone, David T. Breault* and B.D. Humphreys*. Characterization and Fate of Telomerase Expressing Epithelia During Kidney Repair. Journal of the American Society of Nephrology, 22(12):2256-65, 2011. *Co-senior authors. Accompanying editorial. Link to MS
- B.D. Humphreys*, S.C. Czerniak, D.P. DiRocco, W. Hasnain, R. Cheema and J.V. Bonventre. Repair of proximal tubule does not involve specialized progenitors. PNAS, 108(22):9226-31, 2011. Link to MS
- E.S. Robinson, E.V. Khankin, T.K. Choueiri, M.D. Dhawan, M.J. Rogers, S.A. Karumanchi and B.D. Humphreys. Suppression of the Nitric Oxide Pathway in Metastatic Renal Cell Carcinoma Patients Receiving VEGF-Signaling Inhibitors. Hypertension, December, 2010. Link to MS
- J.S. Duffield and B.D. Humphreys. Origin of New Cells in the Adult Kidney: Results from Genetic Labeling Techniques. Kidney International, invited review, 2010.
- E.S.Robinson, U.A. Matulonis, P. Ivy, S.T. Berlin, K. Tyburski, R.T. Penson and B.D. Humphreys. Rapid Development of Hypertension and Proteinuria with Cediranib, an Oral Vascular Endothelial Growth Factor Receptor Inhibitor. Clinical Journal of the American Society of Nephrology, January, 2010.
- B.D. Humphreys, S. Lin, A. Kobayashi, B. Nowlin, T.E. Hudson, J.V. Bonventre, M.T. Valerius, A.P. McMahon and J.S. Duffield. Fate Tracing Reveals the Pericyte and not Epithelial Origin of Myofibroblasts in Kidney Fibrosis. American Journal of Pathology, 176(1):85-97, 2010. Cover art, accompanying commentary and highligted in Faculty of 1000.
- B.D. Humphreys. Slow Cycling Cells in Renal Papilla: Stem Cells Awaken? Journal of the American Society of Nephrology, 20(11)2277-9, 2009.
- B.D. Humphreys, T. Valerius, A. Kobayashi, S. Soeung, J. S. Duffield, A.P. McMahon and J.V. Bonventre. Intrinsic Epithelial Cells Repair the Kidney after Injury. Cell Stem Cell. 2:284-91, 2008. Highlighted in Cell Stem Cell, Kidney International and Faculty of 1000.
- B.D. Humphreys and J.V. Bonventre. “Mesenchymal Stem Cells in Acute Kidney Injury.” Annual Review of Medicine, 59:311-325, 2008. Link to MS
- B.D. Humphreys and J.V. Bonventre. “The Contribution of Adult Stem Cells to Renal Repair.” Nefrologie et Therapeutique, 3:3-10, 2007.
- Full Bibliography
- Contact: Benjamin Humphreys MD, PhD email@example.com