Messina Lab at the University of Massachusetts Medical School
The long term goal of the Messina Lab is to identify the molecular and cellular mechanisms that regulate collateral artery enlargement in order to develop new treatment paradigms for patients with peripheral artery disease. This NIH funded work has shown that remodeling of collateral arteries is dependent on endothelial nitric oxide synthase –nitric oxide bioavailability. Based upon this work, a patent has been submitted for intellectual property that increases nitric oxide bioavailability under conditions of oxidant stress. Despite the critical importance of nitric oxide bioavailability to innumerable signaling pathways, there is no currently available therapy to increase NO bioavailability. We are now developing a Phase 1 clinical trial to determine the safety and efficacy of our molecular therapy.
At the moment, the laboratory is studying the effects of oxidant stress, specifically that of type II diabetes and hypercholesterolemia on mesenchymal and hematopoietic stem cell function. We have recently shown that hyperinsulinemia-induced oxidant stress of mesenchymal stem cells restricts their multipotency and impairs their capacity to augment neovascularization after induction of hind limb ischemia. We have developed techniques to reverse these oxidant-induced impairments of mesenchymal stem cell function.
A second major focus of the Messina Laboratory has been to define a mechanism by which hypercholesterolemia increases the risk of cancer. It has been known for more than three decades that hypercholesterolemia not only increases the risk of death from cardiovascular disease but also all–cause mortality, especially that of colorectal cancer. Over the last number of years we have been able to show a cellular and molecular mechanism that links these two processes. Hypercholesterolemia induces oxidant stress in hematopoietic stem cells that causes an acceleration of their aging and impairs lymphocyte lineage specification that results in a reduced number of γδ T cells and natural killer T cells. This reduction in γδ T cells and natural killer T cell number impairs innate immunity and thereby immunosurveillance against experimentally induced colorectal cancer. Furthermore, we were able to transfer this increased risk of colorectal cancer by transplanting hematopoietic stem cells from hypercholesterolemic mice into lethally irradiated wild type mice. Thus, these results strongly suggest that there is an epigenetic mechanism operant in hematopoietic stem cells that affects the number and function of terminally differentiated cells, the specific effect being dependent on the cause of the oxidant stress.
In order to determine the robustness of the hypothesis that hematopoietic stem cells are sensitive to conditions that cause systemic oxidant stress, we have also shown that type II diabetes impairs hematopoietic stem cell function and impairs lineage specification of monocytes. In a way similar to the process described above, we have shown that the impaired wound healing phenotype of a type II diabetic mouse can be transferred to a wild type mouse by transplanting the hematopoietic stem cells from the type II diabetic mouse into a lethally irradiated wild type recipient.
Over the next year we plan to submit at least one RO1 Grant on the epigenetic effects of cardiovascular risk factors on hematopoietic stem cell differentiation.
- Yan J, Tang GL, Wang R, Messina LM. Optimization of adenovirus-mediated endothelial nitric oxide synthase delivery in rat hindlimb ischemia. Gene Ther. 2005 Nov;12(22):1640-50.
- Yang Y, Tang G, Yan J, Park B, Hoffman A, Tie G, Wang R, Messina LM. Cellular and molecular mechanism regulating blood flow recovery in acute versus gradual femoral artery occlusion are distinct in the mouse. J Vasc Surg. 2008 Dec;48(6):1546-58. PMCID: PMC2791875.
- Yan J, Tie G, Park B, Yan Y, Nowicki PT, Messina LM. Recovery from hind limb ischemia is less effective in type 2 than in type 1 diabetic mice: roles of endothelial nitric oxide synthase and endothelial progenitor cells. J Vasc Surg. 2009 Dec;50(6):1412-22. PMCID: PMC2797079.
- Yan J, Tie G, Hoffman A, Yang Y, Nowicki PT, Messina LM. Oral tetrahydrobiopterin improves the beneficial effect of adenoviral-mediated eNOS gene transfer after induction of hindlimb ischemia. Mol Ther. 2010 Aug;18(8):1482-9. doi: 10.1038/mt.2010.109. PMCID: PMC20551918
- Yan J, Tie G, Wang S, Messina KE, DiDato S, Guo S, Messina LM. Type 2 diabetes restricts multipotency of mesenchymal stem cells and impairs their capacity to augment postischemic neovascularization in db/db mice. J Am Heart Assoc. 2012 Dec;1(6):e002238. PMCID: PMC23316315
- Yan J, Tie G, Messina LM. Tetrahydrobiopterin, L-arginine and vitamin C act synergistically to decrease oxidative stress, increase nitricoxide and improve blood flow after induction of hindlimbischemia in the rat. Mol Med. 2012 May 9;18:676-84. PMCID: PMC3388126.
- Yan J, Tie G, Xu TY, Cecchini K, Messina LM. Mesenchymal stem cells as a treatment for peripheral arterial disease: current status and potential impact of type II diabetes on their therapeutic efficacy. Stem Cell Rev. 2013 Jun;9(3):360-72. PMCID: PMC3683101.
- Tie G, Messina KE, Yan J, Messina JA, Messina LM. Hypercholesterolemia induces oxidant stress that accelerates the ageing of hematopoietic stem cells. J Am Heart Assoc. 2014 Jan 27;3(1):e000241. PMCID: PMC3959695.