Harvard Stem Cell Institute Research Newsletter
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| | | |  | Research Commentary Stem cell based gene delivery strategies; promising leads toward tumor-specific therapies by Lisa Girard, PhD
HSCI Science Editor We continue to learn more about the utility of stem cells as our insights into their fundamental biology expand. For example, in addition to their ability to replace or regenerate damaged tissues or organs, or graft onto surrounding tissues and provide a source for a missing gene product, they can also be used as vectors for the delivery of therapies. There has been significant progress on this latter point in the use of stem cells as therapeutic gene delivery vehicles, specifically in the area of cytotoxic agent delivery to tumors. This progress has been propelled forward largely due to the tumor tropic (i.e. tumor seeking) nature of neural stem cells (NSCs) and mesenchymal stem cells (MSCs). MSCs and NSCs are both types of pluripotent stem cells that, in addition to their tumor tropic properties, have the additional advantage of being relatively amenable to growth in the laboratory, making them more available for use as tools. MSCs are found in the bone marrow and have the ability to differentiate into a number of mesoderm-derived cell types including osteoblasts, chondrocytes, myocytes, and adipocytes. NSCs in the developing brain are capable of producing a number of different neural cell types, depending upon where in the brain they are located. The tumor tropic properties of MSCs and NSCs to home and infiltrate tumors make them ideal candidates for therapeutic gene delivery, increasing the specificity of treatments and thereby raising their therapeutic impact. The ability of these cells to home to areas of pathology, while still not well understood, is mediated by multiple factors – e.g. cytokines, growth factors, receptors, extracellular matrix proteins, and adhesion molecules. Studies by Birnbaum et al. (Birnbaum et al., 2007) examining homing of MSCs to glioma type brain tumors found that glioma brain tumor cells attract MSCs by secreting angiogenic, or blood vessel formation promoting, cytokines. Interestingly, it is the redundancy created by having a multitude of recognition factors that make stem cell based delivery methods potentially so powerful in comparison to, for example, more specific antibody-mediated recognition systems. Stem cells have several additional advantages relative to other vectors as well. Unlike other delivery modes, such as liposomes or nanoparticles, stem cells have the ability to infiltrate a tumor and disperse throughout its mass, making them more likely to produce a significant therapeutic impact. Also, the stem cells can be engineered to survive for a long or short-term span, as necessitated by the application. For example, their use in gene therapy to replace a missing endogenous factor would necessitate long-term survival. However, for chemotherapeutic use to eliminate a defined pathology it would be beneficial if they were only to survive for the short time course of the delivery of the chemotherapy itself. A third advantage of this approach is that NSCs and MSCs appear to home to tumors independent of their size, location, or composition. This is particularly useful because it obviates many of the challenges faced, for example getting drugs into the brain across the blood brain barrier. There are many research groups using stem cell's tumor tropic properties to deliver anti-cancer genes to tumor cells. Khalid Shah of Harvard's Massachusetts General Hospital and his group found in their study of gliomas that the microRNA miR-21 is expressed at higher than normal levels in gliomas (Corsten et al., 2007). The researchers then asked whether eliminating miR-21 would make the glioma tumor cells more sensitive to cytotoxic agents. Using a combination therapy in mice that suppressed miR-21 expression in conjunction with NPCs (note: you haven't defined these or mentioned them as distinct from NSCs) engineered to carry a factor promoting cell death, they were able to eradicate the tumor cells. Medulloblastoma, a pediatric brain tumor with a traditionally poor prognosis, is another type of brain tumor that appears to be a good candidate for stem cell based delivery of therapeutic agents. Rona Carroll's research group at Harvard's Brigham and Women's Hospital (Kim et al., 2006) investigated the utility of stem cell tumor tropism to treat medulloblastomas. Carroll's group asked whether NSCs could migrate specifically to medulloblastomas and tested their ability to serve as a vehicle for therapeutic gene delivery. They engineered NSCs to deliver an inactive prodrug form of the activating enzyme cytosine deaminase and found that the engineered NSCs could indeed effectively home to the medulloblastoma and deliver the therapeutic leading to a significant reduction in tumor size. In addition to brain tumors, stem cells have also been shown to home to other sites of pathology. Yasuo Saijo's group from Tohoku University Graduate School of Medicine in Japan (Xin et al., 2007) showed that MSCs could migrate to lung tumors. The researchers engineered MSCs containing the immunostimulatory factor, CX3CL1, and determined that after intravenous injection of these engineered cells into mice, they could home to lung tumors and significantly inhibit their development. Studies such as these show the range both of tumor types and methods that stem cell based delivery can address. The demonstrated ability of MSCs and NSCs to home specifically to tumors provides a degree of specificity that is not possible with traditional systemically administered chemotherapeutics. Furthermore, these approaches have advantages over more recent attempts at devising localized delivery methods, such as liposomes and antibodies, because of the cells' ability to actually get inside the tumor. This dispersal can raise the therapeutic index while reducing side effects. Given the range of pathologies stem cell based delivery systems can address they are likely to represent a critical and growing facet in treatment strategies in the not too distant future. References - Birnbaum, T., Roider, J., Schankin, C.J., Padovan, C.S., Schichor, C., Goldbrunner, R., Straube, A. (2007). Malignant gliomas actively recruit bone marrow stromal cells by secreting angiogenic cytokines. J Neurooncol. 83, 241-247.
- Corsten, M.F., Miranda, R.., Kasmieh, R., Krichevsky, A.M., Weissleder, R., Shah, K. (2007) MicroRNA-21 knockdown disrupts glioma growth in vivo and displays synergistic cytotoxicity with neural precursor cell delivered S-TRAIL in human gliomas. Cancer Res. 67, 8994-9000.
- Kim, S.K., Kim, S.U., Park, I.H., Bang, J.H., Aboody, K.S., Wang, K.C., Cho, B.K., Kim, M., Menon, L.G., Black, P.M., Carroll, R.S. (2006). Human neural stem cells target experimental intracranial medulloblastoma and deliver a therapeutic gene leading to tumor regression. Clin Cancer Res. 12, 5550-5566.
- Xin H, Kanehira M, Mizuguchi H, Hayakawa T, Kikuchi T, Nukiwa T, Saijo Y. (2007). Targeted delivery of CX3CL1 to multiple lung tumors by mesenchymal stem cells. Stem Cells 25, 1618-1626.
| | | Spotlight Article Intrinsic epithelial cells repair the kidney after injury This month's spotlighted article is by Principal Faculty members Benjamin D. Humphreys, MD, PhD and Joseph V. Bonventre, MD, PhD of Brigham and Women's Hospital, and HSCI Executive Committee Member Andrew McMahon, PhD of Harvard University. Understanding the mechanisms of nephron repair is critical for the design of new therapeutic approaches to treat kidney disease. The kidney can repair after even a severe insult, but whether adult stem or progenitor cells contribute to epithelial renewal after injury and the cellular origin of regenerating cells remain controversial. Using genetic fate-mapping techniques, we generated transgenic mice in which 94%-95% of tubular epithelial cells, but no interstitial cells, were labeled with either beta-galactosidase (lacZ) or red fluorescent protein (RFP). Two days after ischemia-reperfusion injury (IRI), 50.5% of outer medullary epithelial cells coexpress Ki67 and RFP, indicating that differentiated epithelial cells that survived injury undergo proliferative expansion. After repair was complete, 66.9% of epithelial cells had incorporated BrdU, compared to only 3.5% of cells in the uninjured kidney. Despite this extensive cell proliferation, no dilution of either cell-fate marker was observed after repair. These results indicate that regeneration by surviving tubular epithelial cells is the predominant mechanism of repair after ischemic tubular injury in the adult mammalian kidney. Humphreys BD, Valerius MT, Kobayashi A, Mugford JW, Soeung S, Duffield JS, McMahon AP, Bonventre JV. Intrinsic epithelial cells repair the kidney after injury. Cell Stem Cell. 2008 Mar 6;2(3):284-91. Read Abstract. | Review and Commentary Articles - Ferguson MA, Vaidya VS, Bonventre JV. Biomarkers of nephrotoxic acute kidney injury. Toxicology. 2008 Mar 20;245(3):182-93. Epub 2008 Jan 4. Read Abstract.
- Li Q, Gregory RI. MicroRNA Regulation of Stem Cell Fate. Cell Stem Cell. 2008 Mar 6;2(3):195-6. Read Abstract.
- de Koning EJ, Bonner-Weir S, Rabelink TJ. Preservation of beta-cell function by targeting beta-cell mass. Trends Pharmacol Sci. 2008 Mar 20. Read Abstract.
- Kreidberg JA. Integrins and matrix in the glomerulus: old mysteries and new insights. J Am Soc Nephrol. 2008 Apr;19(4):650-1. Epub 2008 Mar 5. Read Abstract.
- Wingert RA, Davidson AJ. The zebrafish pronephros: A model to study nephron segmentation. Kidney Int. 2008 Mar 5. Read Abstract.
- Karra R, Wu SM. Multipotent stem cells in cardiac regenerative therapy. Regen Med. 2008 Mar;3(2):189-98. Read Abstract.
- Williams DA. NIH recombinant DNA Advisory Committee continues to ponder adverse event associated with AAV gene therapy trial. Mol Ther. 2008 Mar;16(3):427-8. Read Abstract.
- Lock EA, Bonventre JV. Biomarkers in translation; past, present and future. Toxicology. 2008 Mar 20;245(3):163-6.. Epub 2007 Dec 17. Read Abstract.
- Scadden DT. Circadian rhythms: stem cells traffic in time. Nature. 2008 Mar 27;452(7186):416-7. Read Abstract.
| Blood - Chae HD, Lee KE, Williams DA, Gu Y. Cross-talk between RhoH and Rac1 in regulation of actin cytoskeleton and chemotaxis of hematopoietic progenitor cells. Blood. 2008 Mar 1;111(5):2597-605. Epub 2007 Dec 18. Read Abstract.
- Pardanani A, Fridley BL, Lasho TL, Gilliland DG, Tefferi A. Host genetic variation contributes to phenotypic diversity in myeloproliferative disorders. Blood. 2008 Mar 1;111(5):2785-9. Epub 2007 Nov 15. Read Abstract.
- Fleming HE, Janzen V, Lo Celso C, Guo J, Leahy KM, Kronenberg HM, Scadden DT. Wnt signaling in the niche enforces hematopoietic stem cell quiescence and is necessary to preserve self-renewal in vivo. Cell Stem Cell.. 2008 Mar 6;2(3):274-83. Read Abstract.
- Rhodes KE, Gekas C, Wang Y, Lux CT, Francis CS, Chan DN, Conway S, Orkin SH, Yoder MC, Mikkola HK. The emergence of hematopoietic stem cells is initiated in the placental vasculature in the absence of circulation. Cell Stem Cell.. 2008 Mar 6;2(3):252-63. Read Abstract.
- Jia Y, Loison F, Hattori H, Li Y, Erneux C, Park SY, Gao C, Chai L, Silberstein LE, Schurmans S, Luo HR. Inositol trisphosphate 3-kinase B (InsP3KB) as a physiological modulator of myelopoiesis. Proc Natl Acad Sci USA. 2008 Mar 25;105(12):4739-44. Epub 2008 Mar 13. Read Abstract.
- Austin KM, Gupta ML, Coats SA, Tulpule A, Mostoslavsky G, Balazs AB, Mulligan RC, Daley G, Pellman D, Shimamura A. Mitotic spindle destabilization and genomic instability in Shwachman-Diamond syndrome. J Clin Invest. 2008 Mar 6. Read Abstract.
| Cancer - Lasho TL, Tefferi A, Hood JD, Verstovsek S, Gilliland DG, Pardanani A. TG101348, a JAK2-selective antagonist, inhibits primary hematopoietic cells derived from myeloproliferative disorder patients with JAK2V617F, MPLW515K or JAK2 exon 12 mutations as well as mutation negative patients. Leukemia. 2008 Mar 20. Read Abstract.
- Thomas EK, Cancelas JA, Zheng Y, Williams DA. Rac GTPases as key regulators of p210-BCR-ABL-dependent leukemogenesis. Leukemia. 2008 Mar 20. Read Abstract.
- Swanson KD, Winter JM, Reis M, Bentires-Alj M, Greulich H, Grewal R, Hruban RH, Yeo CJ, Yassin Y, Iartchouk O, Montgomery K, Whitman SP, Caligiuri MA, Loh ML, Gilliland DG, Look AT, Kucherlapati R, Kern SE, Meyerson M, Neel BG. SOS1 mutations are rare in human malignancies: implications for Noonan Syndrome patients. Genes Chromosomes Cancer. 2008 Mar;47(3):253-9. Read Abstract.
- Langenau DM, Keefe MD, Storer NY, Jette CA, Smith AC, Ceol CJ, Bourque C, Look AT, Zon LI. Co-injection strategies to modify radiation sensitivity and tumor initiation in transgenic Zebrafish. Oncogene. 2008 Mar 17. Read Abstract.
- Costa DB, Schumer ST, Tenen DG, Kobayashi S. Differential responses to erlotinib in epidermal growth factor receptor (EGFR)-mutated lung cancers with acquired resistance to gefitinib carrying the L747S or T790M secondary mutations. J Clin Oncol. 2008 Mar 1;26(7):1182-4; author reply 1184-6. No abstract available. Read Abstract.
| Cardiovascular System - Chan JY, Takeda M, Briggs LE, Graham ML, Lu JT, Horikoshi N, Weinberg EO, Aoki H, Sato N, Chien KR, Kasahara H. Identification of cardiac-specific myosin light chain kinase. Circ Res. 2008 Mar 14;102(5):571-80. Epub 2008 Jan 17. Read Abstract.
- Kontaridis MI, Yang W, Bence KK, Cullen D, Wang B, Bodyak N, Ke Q, Hinek A, Kang PM, Liao R, Neel BG.. Deletion of Ptpn11 (Shp2) in cardiomyocytes causes dilated cardiomyopathy via effects on the extracellular signal-regulated kinase/mitogen-activated protein kinase and RhoA signaling pathways. Circulation. 2008 Mar 18;117(11):1423-35. Epub 2008 Mar 3. Read Abstract.
| Developmental Biology - Stadtfeld M, Maherali N, Breault DT, Hochedlinger K. Defining Molecular Cornerstones during Fibroblast to iPS Cell Reprogramming in Mouse. Cell Stem Cell. 2008 Mar 6;2(3):230-40. Epub 2008 Feb 14. Read Abstract.
- Tullet JM, Hertweck M, An JH, Baker J, Hwang JY, Liu S, Oliveira RP, Baumeister R, Blackwell TK. Direct inhibition of the longevity-promoting factor SKN-1 by insulin-like signaling in C. elegans. Cell. 2008 Mar 21;132(6):1025-38. Read Abstract.
- Punzo C, Cepko CL. Ultrasound-guided in utero injections allow studies of the development and function of the eye. Dev Dyn. 2008 Mar 19;237(4):1034-1042 [Epub ahead of print] Read Abstract.
- Narala SR, Allsopp RC, Wells TB, Zhang G, Prasad P, Coussens MJ, Rossi DJ, Weissman IL, Vaziri H. SIRT1 Acts as a Nutrient-sensitive Growth Suppressor and Its Loss Is Associated with Increased AMPK and Telomerase Activity. Mol Biol Cell. 2008 Mar;19(3):1210-9. Epub 2008 Jan 9. Read Abstract.
- Rajagopal J, Carroll TJ, Guseh JS, Bores SA, Blank LJ, Anderson WJ, Yu J, Zhou Q, McMahon AP, Melton DA. Wnt7b stimulates embryonic lung growth by coordinately increasing the replication of epithelium and mesenchyme. Development. 2008 Mar 26. Read Abstract.
- Kim J, Chu J, Shen X, Wang J, Orkin SH. An extended transcriptional network for pluripotency of embryonic stem cells. Cell. 2008 Mar 21;132(6):1049-61. Read Abstract.
- Paulsen FP, Woon CW, Varoga D, Jansen A, Garreis F, Jäger K, Amm M, Podolsky DK, Steven P, Barker NP, Sel S. ITF/TFF3 promotes re-epithelialization of corneal wounds. J Biol Chem. 2008 Mar 7. Read Abstract.
- Puschendorf M, Terranova R, Boutsma E, Mao X, Isono K, Brykczynska U, Kolb C, Otte AP, Koseki H, Orkin SH, van Lohuizen M, Peters AH. PRC1 and Suv39h specify parental asymmetry at constitutive heterochromatin in early mouse embryos. Nat Genet. 2008 Apr;40(4):411-20. Epub 2008 Mar 2. Read Abstract.
| Diabetes - Marselli L, Thorne J, Ahn YB, Omer A, Sgroi DC, Libermann T, Otu HH, Sharma A, Bonner-Weir S, Weir GC. Gene Expression of Purified {beta}-Cell Tissue Obtained from Human Pancreas with Laser Capture Microdissection. J Clin Endocrinol Metab. 2008 Mar;93(3):1046-53. Epub 2007 Dec 11. Read Abstract.
| Imaging - Hong R, Cima MJ, Weissleder R, Josephson L. Magnetic microparticle aggregation for viscosity determination by MR. Magn Reson Med. 2008 Mar;59(3):515-20. Read Abstract.
- Guimaraes AR, Tabatabei S, Dahl D, McDougal WS, Weissleder R, Harisinghani MG. Pilot Study Evaluating Use of Lymphotrophic Nanoparticle-Enhanced Magnetic Resonance Imaging for Assessing Lymph Nodes in Renal Cell Cancer. Urology. 2008 Mar 4. Read Abstract.
- Figueiredo JL, Passerotti CC, Sponholtz T, Nguyen HT, Weissleder R. A novel method of imaging calcium urolithiasis using fluorescence. J Urol. 2008 Apr;179(4):1610-4. Epub 2008 Mar 4. Read Abstract.
- Sosnovik DE, Nahrendorf M, Weissleder R. Magnetic nanoparticles for MR imaging: agents, techniques and cardiovascular applications. Basic Res Cardiol. 2008 Mar;103(2):122-30. Read Abstract.
- Nahrendorf M, Sosnovik DE, Weissleder R MR-optical imaging of cardiovascular molecular targets. Basic Res Cardiol. 2008 Mar;103(2):87-94. Read Abstract.
| Immunology - Jakubzick C, Tacke F, Ginhoux F, Wagers AJ, van Rooijen N, Mack M, Merad M, Randolph GJ. Blood Monocyte Subsets Differentially Give Rise to CD103+ and CD103- Pulmonary Dendritic Cell Populations. J Immunol. 2008 Mar 1;180(5):3019-27. Read Abstract.
| Pulmonary System - Demchenko IT, Atochin DN, Gutsaeva DR, Godfrey RR, Huang PL, Piantadosi CA, Allen BW. Contributions of Nitric Oxide Synthase Isoforms to Pulmonary Oxygen Toxicity, Local vs. Mediated Effects. Am J Physiol Lung Cell Mol Physiol. 2008 Mar 7. Read Abstract.
| Renal System - Humphreys BD, Valerius MT, Kobayashi A, Mugford JW, Soeung S, Duffield JS, McMahon AP, Bonventre JV. Intrinsic epithelial cells repair the kidney after injury. Cell Stem Cell. 2008 Mar 6;2(3):284-91. Read Abstract.
- Zhang PL, Rothblum LI, Han WK, Blasick TM, Potdar S, Bonventre JV. Kidney injury molecule-1 expression in transplant biopsies is a sensitive measure of cell injury.. Kidney Int. 2008 Mar;73(5):608-14. Epub 2007 Dec 26. Read Abstract.
| Technology - Osafune K, Caron L, Borowiak M, Martinez RJ, Fitz-Gerald CS, Sato Y, Cowan CA, Chien KR, Melton DA. Marked differences in differentiation propensity among human embryonic stem cell lines. Nat Biotechnol. 2008 Mar;26(3):313-5. Epub 2008 Feb 17. Read Abstract.
- Shin M, Abukawa H, Troulis MJ, Vacanti JP. Development of a biodegradable scaffold with interconnected pores by heat fusion and its application to bone tissue engineering. J Biomed Mater Res A. 2008 Mar 1;84(3):702-9. Read Abstract.
- Deutsch EW, Ball CA, Berman JJ, Bova GS, Brazma A, Bumgarner RE, Campbell D, Causton HC, Christiansen JH, Daian F, Dauga D, Davidson DR, Gimenez G, Goo YA, Grimmond S, Henrich T, Herrmann BG, Johnson MH, Korb M, Mills JC, Oudes AJ, Parkinson HE, Pascal LE, Pollet N, Quackenbush J, Ramialison M, Ringwald M, Salgado D, Sansone SA, Sherlock G, Stoeckert CJ Jr, Swedlow J, Taylor RC, Walashek L, Warford A, Wilkinson DG, Zhou Y, Zon LI, Liu AY, True LD. Minimum information specification for in situ hybridization and immunohistochemistry experiments (MISFISHIE). Nat Biotechnol. 2008 Mar;26(3):305-12. Read Abstract.
| The Harvard Stem Cell Institute is a scientific collaborative established to fulfill the promise of stem cell biology as the basis for cures and treatments for a wide range of chronic medical conditions. Visit our website at www.hsci.harvard.edu. If there is anything that you would like to see added to this email alert, please email maureen_lyons@harvard.edu. | |
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