Photo of Robert Sackstein,  MD, PhD

Robert Sackstein, MD, PhD

Brigham And Women's Hospital

Brigham And Women's Hospital
Phone: (617) 525-5604
Fax: (617) 525-5571


rsackstein@rics.bwh.harvard.edu

Robert Sackstein, MD, PhD

Brigham And Women's Hospital

EDUCATIONAL TITLES

  • Professor, Dermatology, Harvard Medical School
  • Professor, Medicine, Harvard Medical School
  • Physician Active Staff, Dermatology and Medicine, Brigham And Women's Hospital
  • Physician, Stem Cell Transplantation Program, Dana-Farber Cancer Institute

DF/HCC PROGRAM AFFILIATION

Research Abstract

In early work, our laboratory identified that L-selectin expression is characteristic not only of lymphocytes but also of early hematopoietic progenitor cells, and this observation led us to examine the expression of L-selectin ligands among human bone marrow cells. These studies led to identification of an L-selectin ligand on early hematopoietic progenitor cells that is structurally distinct from L-selectin ligands expressed on endothelial cells. Subsequent biochemical studies from our laboratory revealed that this ligand, now known as Hematopoietic Cell E-/L-selectin Ligand (HCELL), is the most potent naturally-expressed E- and L-selectin ligand in the body. HCELL is a specialized glycoform of CD44 natively expressed exclusively on human hematopoietic stem cells. Through its role as a potent E-selectin ligand, HCELL functions as the "bone marrow homing receptor" that directs hematopoietic stem cell migration into the marrow. Current studies are aimed at elucidating HCELL's role in hematopoiesis and in the regulation of stem cell homing. In addition, HCELL is characteristically expressed on blasts of acute leukemia, and thus we are investigating how HCELL expression is related to leukemogenesis and how expression of this molecule is regulated on normal stem cells and leukemic blasts. In complementary studies, we have developed reagents to program HCELL expression by ex vivo glycan engineering of surface CD44 and we are examining how enforced HCELL expression licenses the delivery of adult stem cells intravascularly for regenerative therapeutics and how it affects leukemogenesis. Another focus of our laboratory is to elucidate the physiology of lymphocyte migration following hematopoietic stem cell transplantation (HSCT). We have obtained evidence that the migration of lymphocytes to lymph nodes post-HSCT is disturbed in part because of disordered regulation of lymphocyte L-selectin gene expression. We are examining the molecular basis of altered L-selectin expression, and, moreover, we are studying how pathologic tissue-specific migration patterns develop post-transplant. In particular, acute graft-versus-host disease (GVHD) following allogeneic HSCT is characterized by the directed migration of alloreactive lymphocytes into three principal target tissues - skin, liver and gut - wherein they mediate tissue destruction. Our laboratory is investigating the adhesion molecules that regulate skin-specific migration of lymphocytes in cutaneous GVHD reactions, in order to elucidate the molecular basis of this process and develop therapeutic agents to treat or prevent cutaneous GVHD. Our overall aim in these studies is to devise novel therapies to eliminate the detrimental GVHD reaction of allogeneic transplantation without disturbing beneficial immune reactions such as the graft-versus-malignancy effect. In other studies, we are investigating the structural biology of key molecules which mediate adhesive interactions that create microenvironmental "niches" for tumor cell proliferation, the adhesion molecules which allow for tumor cell dissemination, and the adhesion molecules that regulate lymphocyte trafficking to sites of tumor. The goal in these studies is to utilize structural information for the rational design of drugs that disrupt adhesion molecules critical for tumor cell growth and metastasis, and that improve immune effector cell infiltration of tumor tissue.

Publications

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  • Sackstein R. Translational glycobiology: Patient-oriented glycoscience research. Glycobiology 2016; 26:544-5. PubMed
  • Agre P, Bertozzi C, Bissell M, Campbell KP, Cummings RD, Desai UR, Estes M, Flotte T, Fogleman G, Gage F, Ginsburg D, Gordon JI, Hart G, Hascall V, Kiessling L, Kornfeld S, Lowe J, Magnani J, Mahal LK, Medzhitov R, Roberts RJ, Sackstein R, Sarkar R, Schnaar R, Schwartz N, Varki A, Walt D, Weissman I. Training the next generation of biomedical investigators in glycosciences. J Clin Invest 2016; 126:405-8. PubMed
  • Merzaban JS, Imitola J, Starossom SC, Zhu B, Wang Y, Lee J, Ali AJ, Olah M, Abuelela AF, Khoury SJ, Sackstein R. Cell surface glycan engineering of neural stem cells augments neurotropism and improves recovery in a murine model of multiple sclerosis. Glycobiology 2015. PubMed
  • Lee J, Dykstra B, Sackstein R, Rossi DJ. Progress and obstacles towards generating hematopoietic stem cells from pluripotent stem cells. Curr Opin Hematol 2015; 22:317-23. PubMed
  • Abdi R, Moore R, Sakai S, Donnelly CB, Mounayar M, Sackstein R. HCELL Expression on Murine MSC Licenses Pancreatotropism and Confers Durable Reversal of Autoimmune Diabetes in NOD Mice. Stem Cells 2015. PubMed
  • Sackstein R, Fuhlbrigge R. Western blot analysis of adhesive interactions under fluid shear conditions: the blot rolling assay. Methods Mol Biol 2015; 1312:399-410. PubMed
  • Batal I, Azzi J, Mounayar M, Abdoli R, Moore R, Lee JY, Rosetti F, Wang C, Fiorina P, Sackstein R, Ichimura T, Abdi R. The mechanisms of up-regulation of dendritic cell activity by oxidative stress. J Leukoc Biol 2014. PubMed
  • Silvescu CI, Sackstein R. G-CSF induces membrane expression of a myeloperoxidase glycovariant that operates as an E-selectin ligand on human myeloid cells. Proc Natl Acad Sci U S A 2014; 111:10696-701. PubMed
  • Dauber A, Ercan A, Lee J, James P, Jacobs PP, Ashline DJ, Wang SR, Miller T, Hirschhorn JN, Nigrovic PA, Sackstein R. Congenital disorder of fucosylation type 2c (LADII) presenting with short stature and developmental delay with minimal adhesion defect. Hum Mol Genet 2014. PubMed
  • Peter Y, Sen N, Levantini E, Keller S, Ingenito EP, Ciner A, Sackstein R, Shapiro SD. CD45/CD11b positive subsets of adult lung anchorage-independent cells harness epithelial stem cells in culture. 2013. PubMed
  • Sackstein R. Re: "Ex vivo fucosylation improves human cord blood engraftment in NOD-SCID IL-2Rγ(null) mice". Exp Hematol 2012. PubMed
  • Sackstein R. Engineering cellular trafficking via glycosyltransferase-programmed stereosubstitution. Ann N Y Acad Sci 2012. PubMed
  • Sackstein R. Glycoengineering of HCELL, the human bone marrow homing receptor: sweetly programming cell migration. Ann Biomed Eng 2012; 40:766-76. PubMed
  • Jansen AJ, Josefsson EC, Rumjantseva V, Liu QP, Falet H, Bergmeier W, Cifuni SM, Sackstein R, von Andrian UH, Wagner DD, Hartwig JH, Hoffmeister KM. Desialylation accelerates platelet clearance after refrigeration and initiates GPIbα metalloproteinase-mediated cleavage in mice. Blood 2012; 119:1263-73. PubMed
  • Jacobs PP, Sackstein R. CD44 and HCELL: preventing hematogenous metastasis at step 1. FEBS Lett 2011; 585:3148-58. PubMed
  • Merzaban JS, Burdick MM, Gadhoum SZ, Dagia NM, Chu JT, Fuhlbrigge RC, Sackstein R. Analysis of glycoprotein E-selectin ligands on human and mouse marrow cells enriched for hematopoietic stem/progenitor cells. Blood 2011; 118:1774-83. PubMed
  • Sackstein R. The biology of CD44 and HCELL in hematopoiesis: the 'step 2-bypass pathway' and other emerging perspectives. Curr Opin Hematol 2011; 18:239-48. PubMed
  • Thankamony SP, Sackstein R. Enforced hematopoietic cell E- and L-selectin ligand (HCELL) expression primes transendothelial migration of human mesenchymal stem cells. Proc Natl Acad Sci U S A 2011; 108:2258-63. PubMed
  • Sackstein R. Hitting the sweet spot for lymphoma. Blood 2010; 115:4626-7. PubMed
  • Chester R, Sackstein R. Embryonic stem cell-based therapeutics: balancing scientific progress and bioethics. Health Matrix Clevel 2010; 20:203-17. PubMed
  • Sackstein R. Directing stem cell trafficking via GPS. Methods Enzymol 2010; 479:93-105. PubMed
  • Lee JY, Buzney CD, Poznansky MC, Sackstein R. Dynamic alterations in chemokine gradients induce transendothelial shuttling of human T cells under physiologic shear conditions. J Leukoc Biol 2009; 86:1285-94. PubMed
  • Sackstein R. Glycosyltransferase-programmed stereosubstitution (GPS) to create HCELL: engineering a roadmap for cell migration. Immunol Rev 2009; 230:51-74. PubMed
  • Nigro J,Wang A,Mukhopadhyay D,Lauer ME,Midura RJ,Sackstein R,Hascall VC. Regulation of heparan sulfate and chondroitin sulfate glycosaminoglycan biosynthesis by 4-fluoro-glucosamine in murine airway smooth muscle cells. J Biol Chem 2009. PubMed
  • Sackstein R,Fuhlbrigge R. Western Blot Analysis of Adhesive Interactions under Fluid Shear Conditions: The Blot Rolling Assay. Methods Mol Biol 2009; 536:343-54. PubMed
  • Gadhoum SZ,Sackstein R. CD15 expression in human myeloid cell differentiation is regulated by sialidase activity. Nat Chem Biol 2008; 4:751-7. PubMed
  • Ngo HT, Leleu X, Lee J, Jia X, Melhem M, Runnels J, Moreau AS, Burwick N, Azab AK, Roccaro A, Azab F, Sacco A, Farag M, Sackstein R, Ghobrial IM. SDF-1/CXCR4 and VLA-4 interaction regulates homing in Waldenstrom Macroglobulinemia. Blood 2008; 112:150-8. PubMed
  • Resto VA, Burdick MM, Dagia NM, McCammon SD, Fennewald SM, Sackstein R. L-selectin-mediated lymphocyte-cancer cell interactions under low fluid shear conditions. J Biol Chem 2008; 283:15816-24. PubMed
  • Shaulov A, Yue S, Wang R, Joyce RM, Balk SP, Kim HT, Avigan DE, Uhl L, Sackstein R, Exley MA. Peripheral blood progenitor cell product contains Th1-biased noninvariant CD1d-reactive natural killer T cells: Implications for posttransplant survival. Exp Hematol 2008; 36:464-72. PubMed
  • Sackstein R, Merzaban JS, Cain DW, Dagia NM, Spencer JA, Lin CP, Wohlgemuth R. Ex vivo glycan engineering of CD44 programs human multipotent mesenchymal stromal cell trafficking to bone. Nat Med 2008; 14:181-7. PubMed
  • Parmar K, Mauch P, Vergilio JA, Sackstein R, Down JD. Distribution of hematopoietic stem cells in the bone marrow according to regional hypoxia. Proc Natl Acad Sci U S A 2007; 104:5431-6. PubMed
  • Schreiber TH, Shinder V, Cain DW, Alon R, Sackstein R. Shear flow-dependent integration of apical and subendothelial chemokines in T-cell transmigration: implications for locomotion and the multistep paradigm. Blood 2006; 109:1381-6. PubMed
  • Dagia NM, Gadhoum SZ, Knoblauch CA, Spencer JA, Zamiri P, Lin CP, Sackstein R. G-CSF induces E-selectin ligand expression on human myeloid cells. Nat Med 2006; 12:1185-90. PubMed
  • Burdick MM, Chu JT, Godar S, Sackstein R. HCELL is the major E- and L-selectin ligand expressed on LS174T colon carcinoma cells. J Biol Chem 2006; 281:13899-905. PubMed
  • Fuhlbrigge RC, King SL, Sackstein R, Kupper TS. CD43 is a ligand for E-selectin on CLA+ human T cells. Blood 2006; 107:1421-6. PubMed
  • Hanley WD, Napier SL, Burdick MM, Schnaar RL, Sackstein R, Konstantopoulos K. Variant isoforms of CD44 are P- and L-selectin ligands on colon carcinoma cells. FASEB J 2006; 20:337-9. PubMed
  • Sackstein R. A Revision of Billingham's Tenets: The Central Role of Lymphocyte Migration in Acute Graft-versus-Host Disease. Biol Blood Marrow Transplant 2006; 12:2-8. PubMed
  • Sackstein R, Fuhlbrigge R. The blot rolling assay: a method for identifying adhesion molecules mediating binding under shear conditions. Methods Mol Biol 2006; 341:217-26. PubMed
  • Sackstein R. The lymphocyte homing receptors: gatekeepers of the multistep paradigm. Curr Opin Hematol 2005; 12:444-50. PubMed
  • Hanley WD, Burdick MM, Konstantopoulos K, Sackstein R. CD44 on LS174T colon carcinoma cells possesses E-selectin ligand activity. Cancer Res 2005; 65:5812-7. PubMed
  • Dey BR, McAfee S, Colby C, Cieply K, Caron M, Saidman S, Preffer F, Shaffer J, Tarbell N, Sackstein R, Sachs D, Sykes M, Spitzer TR. Anti-tumour response despite loss of donor chimaerism in patients treated with non-myeloablative conditioning and allogeneic stem cell transplantation. Br J Haematol 2005; 128:351-9. PubMed
  • Sackstein R. The bone marrow is akin to skin: HCELL and the biology of hematopoietic stem cell homing. J Investig Dermatol Symp Proc 2004; 9:215-23. PubMed
  • Dimitroff CJ, Kupper TS, Sackstein R. Prevention of leukocyte migration to inflamed skin with a novel fluorosugar modifier of cutaneous lymphocyte-associated antigen. J Clin Invest 2003; 112:1008-18. PubMed
  • Dimitroff CJ, Bernacki RJ, Sackstein R. Glycosylation-dependent inhibition of cutaneous lymphocyte-associated antigen expression: implications in modulating lymphocyte migration to skin. Blood 2002; 101:602-10. PubMed
  • Fuhlbrigge RC, King SL, Dimitroff CJ, Kupper TS, Sackstein R. Direct real-time observation of E- and P-selectin-mediated rolling on cutaneous lymphocyte-associated antigen immobilized on Western blots. J Immunol 2002; 168:5645-51. PubMed
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