Project 1

Function of Lactosaminyl Glycans in Early Hematopoietic and Myelopoietic Cells

Abstract

A basic question in hematology is how adhesive receptor-ligand interactions are created and regulated within bone marrow microenvironments. The ordered engagement of adhesion molecules governs the homing of hematopoietic progenitors into the marrow, the proliferation and differentiation of progenitors into blood cells, and the egress of both progenitors and mature blood cells into the vasculature. The proliferation of malignant blood cells is also critically dependent on the combinatorial and temporal expression of adhesion molecules that create relevant growth niches within the marrow. Cell surface lactosaminyl glycans, particularly those bearing terminal sialic acid and fucose modifications, serve as principal effectors, as well as modulators, of a variety of adhesive interactions critical to hematopoiesis. Conspicuously, the expression of these structures within hematopoietic cells of marrow varies distinctly in a stage-specific and lineage-specific manner. In this project, we seek to characterize the lactosaminyl glycans expressed on human cells at the transition between primitive progenitors and early myeloid and non-myeloid progenitor cells, and the pertinent protein and/or lipid scaffolds that present these glycans. We will analyze the function(s) of these structures in licensing adhesive interactions critical to early hematopoietic lineage commitment, with emphasis on myelopoiesis, and will examine how they mediate interactions between hematopoietic cells and supportive marrow stromal cells (“mesenchymal stem cells”, MSCs). These studies will address fundamental questions regarding the molecular basis of hematopoiesis in humans. It is anticipated that the information obtained will yield strategies to modulate expression of key terminal lactosaminyl glycans to achieve the overarching clinical goals of enhancing myelopoietic recovery following myelosuppressive/myeloablative chemoradiotherapy, of stimulating hematopoiesis in conditions of marrow failure, and of halting dysregulated myeloproliferation such as in leukemia.

Robert Sackstein, M.D., Ph.D. is a bone marrow transplant physician and biomedical researcher. He received his undergraduate degree from Harvard College, Summa cum Laude in Biology, and his M.D. and Ph.D. degrees from Harvard Medical School, where he also received the James Tolbert Shipley Prize for outstanding research. He then completed internal medicine training and fellowships in immunology and hematology at the University of Miami, and received the Young Investigator Award for Excellence in the Field of Hematology from the International Society for Experimental Hematology. Dr. Sackstein’s efforts have helped define the processes that regulate the movement of blood-borne cells into different tissues throughout the body. In particular, he is widely recognized for contributions to our understanding of adhesion molecules that regulate cellular trafficking, and for developing a platform technology (known as “GPS”) for programming stem cell migration to sites of tissue injury. He is a Professor in the Departments of Dermatology and of Medicine at Harvard Medical School. He is a Bone Marrow Transplant Physician at Brigham and Women’s Hospital and the Dana-Farber Cancer Institute, and also serves as the Co-Director of the Graduate Education in Medical Sciences (GEMS) program at the Massachusetts Institute of Technology. When not treating patients, teaching and/or performing research, Dr. Sackstein relishes time spent with his family and friends, is hooked on “The Simpsons,” and eats chocolate ice cream for breakfast.

 

Dr. Nandini Mondal received her Bachelor’s and Master’s degree in Chemical Engineering from Indian Institute of Technology, Kharagpur, following which she pursued her doctoral studies under the supervision of Dr. Sriram Neelamegham at SUNY, Buffalo. During her doctoral research she developed a microfluidic assay system to mimic (ex vivo) the bio-chemical and bio-mechanical micro-environment within a blood vessel. She also received training in gene silencing (using RNAi) and genomic editing (using CRISPR/Cas). With the above tools Nandini studied the roles of key Glycosyltransferases (GlycoTs) in regulating the rolling phenotype of human leukocytes on stimulated endothelial cells. Nandini joined the Sackstein research group as a post-doctoral fellow in September 2014 where she endeavors to use her multi-disciplinary experience to solve scientific problems in clinical research. Her current focus is on studying the relative expression levels of GlycoTs contributing in E-selectin ligand synthesis in the earliest hematopoietic stem and progenitor cells. Outside the lab, Nandini likes to indulge her creative side through painting, dancing, cooking and reading. She is particularly interested in reading about mythologies from different cultures around the globe.

Dr. Gisela Pachon is a native of Colombia, and received her Ph.D. in Biochemistry and Molecular Biology from the University of Barcelona, Spain, under the supervision of Dr. Marta Cascante. During her doctoral research, Dr. Pachon characterized anitumor drug effects and studied the differences of glucose regulation metabolism among normal and different tumor cell lines. In 2009, Dr. Pachon began postdoctoral research work in the laboratory of Dr. Joan Vendrell in Tarragona, Spain, where she studied the isolation, characterization and differentiation of potential stem cells derived from human adipose tissue. Dr. Pachon has joined Dr. Sackstein’s lab to examine how enforced Hematopoietic Cell E- and L-Selectin ligand (HCELL) expression on adipose-derived stem cells and on hematopoietic stem cells creates the hematopoietic “niche.” In her free time, Gisela enjoys a good meal with her friends, catching the latest comedy movie in theaters, and watching her fellow Colombian, Sofia Vergara, in her U.S. sitcom.

Mariana da Silva

Mariana da Silva received her Bachelor’s degree in Cellular and Molecular Biology and Master’s degree in Molecular Genetics and Biomedicine from Faculty of Science and Technology, Nova University of Lisbon, following which she pursued her doctoral studies under the supervision of Dr. Paula Videira at Faculty of Medical Science, Nova University of Lisbon, and of Dr. Robert Sackstein. During her doctoral research she has identified and characterized several E-selectin ligands expressed by different blood cell types, including monocytes, lymphocytes and Dendritic Cells. Currently she is studying the expression of different glycosyltransferases that are involved in E-selectin ligand epitopes formation in mature blood cell types. Outside the lab, she likes to spend time with friends, travel, read and watch portuguese soccer.

Kyle Martin

Kyle Martin returned to school after 12 plus years of construction experience and received his Bachelor of Science degree in Biology at the State University of New York at Plattsburgh in 2006.  After graduation, he worked as a technician in an immunology lab at the Trudeau Institute in Saranac Lake, NY, and in 2008 was offered a technical research associate position at the University of Rochester Medical Center in Rochester, NY. In 2015 he left Rochester and returned home to Framingham, MA.  He was offered a position as Senior Technical Research Assistant/lab manager with the Sackstein Lab at the end of 2015 and joined full time in January of 2016.  Outside of the lab, he enjoys various sports, fishing, camping, gardening, cooking and good beer/wine.

 

Dr. Brittany Pequegnat received her Ph.D. in Chemistry in 2016 from the University of Guelph under the supervision of Prof. Mario A Monteiro in Guelph, Canada. During her doctoral studies Brittany worked to characterize bacterial capsular polysacchrides from bacteria related to gastrointestinal aliments using mass spectral analysis and nuclear magnetic resonance. Her efforts during her Ph.D. contributed to the overall goal of the research group to develop a multi-valent vaccine for Campylobacter jejuni. For the C. jejuni research Dr. Pequegnat worked in collaboration with the U.S. Naval Medical Research Center’s Department of Enteric Diseases, with whom she is working on patenting some of her most recent academic findings. During her M.Sc. Dr. Pequegnat worked with Clostridium bolteae, an autism associated bacterium. She successfully characterized the C. bolteae capsular polysaccharide structure and established the first diagnostic target against it. Dr. Pequegnat joined the Sackstein laboratory January of 2017. When she isn’t in the lab you can find Brittany out running, at the gym, or watching her Toronto sports teams.

 

Contact Information:
Robert Sackstein, M.D., Ph.D.
Harvard Institutes of Medicine
77 Avenue Louis Pasteur, Suite 671
Boston, Massachusetts 02115
Office Number: 617-525-5604
Email: rsackstein@rics.bwh.harvard.edu