David Hess, Scientist, Molecular Medicine: Vascular and Brain Health Group, Krembil Centre for Stem Cell Biology, Robarts Research Institute, Associate Professor, Department of Physiology and Pharmacology, UWO
Why I Became a Scientist
Growing up I was always interested in a career in medicine. As a teen I underwent bone marrow transplantation to treat severe aplastic anemia, a disease where stem cells within the bone marrow fail to produce red blood cells that carry oxygen to our tissues, leukocytes that fight infection, and platelets involved in blood coagulation. As a result, my focus and interest in stem cells and transplantation therapy was initiated. During my undergraduate and post-graduate education, I was fascinated by the immense potential of stem cell transplantation to treat a wide variety of potentially fatal diseases. Ultimately, I focused on the exciting field of stem cell research as my career path in order to develop cellular therapies for cancer, cardiovascular diseases, and diabetes. I feel my experiences as both a patient and a research scientist allows for a unique perspective in the preclinical and clinical development of cellular therapies.
The focus of Dr. Hess’s research is to understand the mechanisms by which distinct stem cell subsets co-ordinate hematopoiesis, angiogenesis, and tissue repair. Ultimately, Dr. Hess is interested in the development of cellular therapies to mediate the repair of diseased, damaged, or ischemic tissues. Specific applications for his work include the use of transplanted human stem cells to promote wound healing and blood vessel formation, and to regenerate insulin-producing beta cells during diabetes.
In an attempt to isolate and study the regenerative functions of human bone marrow-derived stem cells, Dr. Hess' lab has purified multiple (hematopoitic, endothelial, and mesenchymal) stem cell lineages simultaneously using high-speed fluorescence activated cell sorting based on a conserved stem cell function (high aldehyde dehydrogenase activity) and cell surface markers. These progenitor cell lineages can be expanded efficiently in vitro and their regenerative functions are studied by the transplantation in immune deficient mouse models specifically designed to track the contributions of human cells during blood vessel formation during critical limb ischemia, and during the regeneration of islet function in hyperglycemic recipients.
Research Questions and Disease Implications
Can the transplantation of purified stem cells promote new blood vessel formation in ischemic tissues?
During diabetes and cardiovascular disease, damage to the cardiovascular system can result in ischemic heart disease and critical limb ischemia. Approximately 14 million individuals in North Americas suffer from ischemic heart disease, and greater than 100,000 diabetic patients will suffer limb amputation due to severe peripheral vascular disease. We have shown that several stem cell types co-ordinate together in the formation of new blood vessels. Ultimately, our goal is to optimize the selection and expansion of rare vessel–forming endothelial progenitor cells, and co-transplant them with supportive hematopoietic and mesenchymal stem cells to augment blood vessel regeneration in vivo.
Can the transplantation of purified stem cells support the regeneration of pancreatic beta-cell function during diabetes?
Diabetes involves a progressive loss of insulin-secreting beta cells within islets of Langerhans, and affects >250 million individuals worldwide. Islet transplantation can establish insulin-independence in severe diabetics, but critical shortages of donor tissue limits its widespread availability. However, regenerative therapies for diabetes are not limited to direct replacement of beta cells. We have established that aldehyde dehydrogenase expressing mixed progenitor cells from human umbilical cord blood and bone marrow mesenchymal stem cells (MSC) recruit to damaged islets after transplantation, induce proliferation of host beta cells, and enhance insulin secretion and glycemic control. We intend to identity how readily available stem cell populations can impact beta cell regeneration, a critical step towards the development of successful cellular therapies for diabetes.
What are the mechanisms by which distinct stem cell subsets co-ordinate complex biological processes such as tissue regeneration?
Although our research program focuses on the regeneration of blood vessels and beta cells to treat the complications of diabetes, the processes of angiogenesis and islet repair are applicable to multiple tissues and disease states. For example, further understanding of blood vessel formation may be useful in the development of cancer therapies to prevent solid tumour growth and vascularization. In addition, the formulation of a regenerative niche by the direct transplantation of pro-angiogenic and islet neogenic stem cells into the pancreas may be used to tip the balance in favour of islet regeneration versus destruction during diabetes. By understanding the ability of transplanted stem cells to mediate regenerative processes we hope to indentify critical secreated molecules and pathways to help the body heal and regenerate itself.
• PhD, Department of Pharmacology and Toxicology, University of Western Ontario, London, ON
• Post-doctoral Research Fellow, Stem Cell Biology and Regenerative Medicine, Robarts Research Institute, London, ON
• Post-doctoral Research Fellow/Research Associate, Department of Internal Medicine, Division of Oncology, Hematopoietic Development and Malignancy Group, Washington University School of Medicine, St. Louis, MO, USA
• MacDonald Scholarship, Heart and Stroke Foundation of Canada
• New Investigator Salary Award, Heart and Stroke Foundation of Canada
• Postdoctoral Fellowship, Canadian Institutes of Health Research
• Postdoctoral Fellowship, Ontario Research and Development Challenge Fund
• Harry and Gundrun Sharma Award for Research Excellence, Department of Pharmacology and Toxicology, The University of Western Ontario
• Medical Research Council PhD. Studentship, National Health Research and Development Program, Health Canada
• Medical Research Council MSc. Studentship, National Health Research and Development Program, Health Canada
• Majumder M, Landman EO, Liu L, Hess DA, Lala PK. COX-2 elevates oncogenic miR-526b in breast cancer by EP4 activation. (2015) Molecular Cancer Research 13(6):1022-1033.
• Hess DA. Periostin conditions the matrix to generate a niche for islet regeneration. (2015) Endocrinology 156(3):772-776.
• Patel P, Brooks C, Seneviratne AK, Hess DA, Seguin CA. Investigating microenvironmental regulation of human chordoma cell behavior. (2015) PLoS One 9(12):e115909.
• Christie DA, Xu LS, Turkistany SA, Solomon SA, Li SK, Welch I, Bell GI, Hess DA, DeKoter RP. PU.1 opposes IL-7-dependent proliferation of developing B cells with involvement of the direct target gene Bruton Tyrosine Kinase. (2015) Journal of Immunology 194(2):595-605.
• Patterson KG, Dixon Pittaro JL, Bastedo PS, Hess DA, Haeryfar SM, McCormick JK. Control of established colon cancer xenografts using a novel humanized single chain antibody-streptococcal superantigen fusion protein targeting the 5T4 oncofetal antigen. (2014) PLoS One 9(4):e95200.
• Bell GI, Seneviratne AKM, Nasri G, Hess DA. Transplantation models to characterize the mechanisms of stem cell-induced islet regeneration. (2014) Current Protocols in Stem Cell Biology 26(2B): 4.1-4.35.
• Zilotto R, Gruca MR, Podder S, Noel G, Ogle CK, Hess DA, DeKoter RP. PU.1 promotes cell cycle exit in the murine myeloid lineage associated with down-regulation of E2F1. (2014) Experimental Hematology 42(3):204-217.
• Li J, Feng ZC, Yeung FS, Wong MR, Oakie A, Fellows GF, Goodyear CG, Hess DA, Wang R. Aldehyde dehydrogenase 1 activity in the developing human pancreas modulates retinoic acid signaling to mediate islet differentiation and survival. (2014) Diabetologia 57(4):754-764.
• Quail DF, Zhang G, Findlay SD, Hess DA, Postovit LM. Nodal promotes invasive phenotypes via a mitogen activated protein kinase-dependent pathway. (2014) Oncogene 23(33):461-473.
• Gillespie JR, Bush JR, Bell GI, Aubrey LA, Dupuis H, Ferron M, Kream B, DiMattia G, Patel S, Woodgett JR, Karsenty G, Hess DA, Beier F. GSK-3β function in bone regulates skeletal development, whole body metabolism and male life span. (2013) Endocrinology 154(10): 3702-3718.
• Putman DM, Hess DA. Isolation of human umbilical cord blood aldehyde dehydrogenase expressing progenitor cells that modulate vascular regenerative functions in vitro and in vivo. (2013) Current Protocols in Stem Cell Biology Chapter 2 Unit (2A):10.1–10.19.
• Noad J, Gonzalez-Lara LE, Broughton HC, McFadden C, Chen Y, Hess DA, Foster PJ. MRI tracking of transplanted iron-labeled mesenchymal stromal cells in an immune-compromised mouse model of critical limb ischemia. (2013) NMR in Biomedicine 26: 458–467.
• Quail DF, Zhang G, Walsh LA, Siegers GM, Dieters-Castador DZ, Findlay SD, Broughton H, Putman DM, Hess DA, Postovit LM. Embryonic morphogen nodal promotes breast cancer growth and progression. (2012) PLoS One 7(11): e48237.
• Putman DM, Liu KY, Broughton HC, Bell GI, Hess DA. Umbilical cord blood-derived aldehyde dehydrogenase-expressing progenitor cells promote recovery from acute ischemic injury. (2012) Stem Cells 30(10): 2248-2260.
• Quail DF, Walsh LA, Zhang G, Findlay SD, Moreno J, Fung L, Ablack A, Lewis JD, Done SJ, Hess DA, Postovit L-M. Embryonic protein nodal promotes breast cancer vascularization. (2012) Cancer Research 72(15):3851-3863.
• Bell GI, Meschino MT, Hughes-Large JM, Broughton HC, Xenocostas A, Hess DA. Combinatorial human progenitor cell transplantation optimizes islet regeneration through secretion of paracrine factors. (2012) Stem Cells and Development 21(11):1863-1876.
• Bell GI, Putman DM, Hughes-Large JM, Hess DA. Intra-pancreatic delivery of human umbilical cord blood aldehyde dehydrogenase expressing cells formulates a niche for endogenous islet regeneration. (2012) Diabetologia 55(6):1755-1760.
• Bell GI, Broughton HC, Levac KD, Allan DA, Xenocostas A, Hess DA. Trasnplanted human progeinotr subtypes stimulate endogenous islet regeneration and revascularization. (2012) Stem Cells and Development 2(4):97-109.
• Capoccia, BJ, Robson DL, Levac KD, Maxwell DJ, Hohm SA, Neelamkavil M, Bell GI, Xenocostas A, Link DC, Piwnica-Worms D, Nolta JA, Hess DA. Revascularization of ischemic limbs by human bone marrow cells purified by aldehyde dehydrogenase activity. (2009) Blood 113(21):5340-5351.
• Croker AK, Goodale D, Chu J, Postenka CO, Hedley BD, Hess DA, Allan AL. High aldehyde dehydrogenase activity and CD44 expression selects for stem-like breast cancer cells with enhanced malignant and metastatic properties. (2009) Journal of Cellular and Molecular Medicine 13(8b):2236-2252.
• Hess DA, Craft TP, Wirthlin L, Hohm SA, Zhou P, Eades W, Creer MH, Sands MS, Nolta JA. Widespread nonhematopoietic tissue distribution by transplanted human progenitor cells with high aldehyde dehydrogenase activity (2008) Stem Cells 26(3):611-620.
• Hess DA, Wirthlin L, Craft TP, Herrbrich PE, Hohm SA, Lahey R, Eades WC, Creer MH, Nolta JA. Selection based on CD133 and high aldehyde dehydrogenase activity isolates long-term reconstituting human hematopoietic stem cells. (2006) Blood 107(5):2162-2169.
• Hess DA, Meyerrose TE, Wirthlin L, Craft TP, Herrbrich PE, Creer MH, Nolta JA. Functional characterization of highly purified human hematopoietic repopulating cells isolated according to aldehyde dehydrogenase activity. (2004) Blood 104(6):1648-1655.
• Hess DA, Li L, Martin M, Sakano S, Hill D, Strutt B, Thyssen S, Gray DA, and Bhatia M. Bone marrow-derived stem cells initiate pancreatic regeneration. (2003) Nature Biotechnology 21(7):763-770.
David A. Hess PhD
Associate Professor, Department of Physiology and Pharmacology
The University of Western Ontario
Scientist, Molecular Medicine: Vascular and Brain Health Group
Krembil Centre for Stem Cell Biology
Robarts Research Institute
1151 Richmond St. N., Room 4245B
London, Ontario, Canada, N6A 5B7
Phone 519-931-5777 x 24152
For General Inquiries Please Contact:
Robarts Research Institute
1151 Richmond St. N., Room 3200
London, Ontario, Canada, N6A 5B7
Phone 519-931-5777 x 24118