Accelerated Repair of Vascular Injury in Diabetes by TGF-beta Modified Stem Cells Abstract: Stem cells of hematopoietic origin (HSC) have been described that have the potential to repair vascular injury (CD34+ stem cells). We have recently demonstrated that a blockade of endogenous transforming growth factor-beta type 1 (TGF-21) in murine and human hematopoietic stem cells accelerates bone marrow engraftment while dramatically reducing the number of HSC needed for long-term reconstitution. CD34+ stem cells can give rise to endothelial progenitor cells (EPC), which have been shown to repair damaged blood vessels. CXCR4 are homing receptors expressed on EPC. Stromal derived factor (SDF)-1 is a chemoattractant released by damaged blood vessels that helps guide EPCs to these damaged sites. TGF-21 has been shown not only to downregulate SDF-1 in damaged blood vessels but also downregulate its receptor (CXCR4) on CD34+/EPC leading to detrimental effects on vessel repair. Importantly, we have recently demonstrated that CD34+/EPC from diabetic patients are markedly defective in their ability to repair damaged vessels and that their migratory response to SDF-1 is markedly reduced. Overall Hypothesis: Transient blockade of endogenous transforming growth factor- beta type 1 (TGF-21) using antisense phosphorodiamidate morpholino oligomers (PMOs) to TGF- 21 in diabetic EPC will restore their ability to repair cardiac damage. The clinical significance of this hypothesis is further supported by observations in the African-American population: 1) HSC isolated from African-Americans with diabetes produce more TGF-21 than normal controls, suppressing their ability to repair damaged vessels. 2) Serum TGF-2 levels are markedly elevated in African-Americans, further suppressing their ability to repair damaged vessels and 3) As a group, African-Americans have a markedly increased risk of cardiovascular disease as compared to Caucasians. This proposal utilizes these novel observations to test these hypotheses applicable to the repair of diabetes-induced vascular injury mediated by CD34+/EPCs. Furthermore, current cellular therapies as well as mechanical therapies such as stents may not benefit this at risk population because of high TGF-21 levels, which can lead to CD34+/EPC dysfunction. The ability to reverse this defect by transient blockade of TGF-2 expression in these CD34+/EPC cells could be sufficient to improve vascular repair of infarcted coronary tissue in not only diabetic African- Americans but also the population as a whole.
Public Health Relevance: This research proposal aims to treat diabetic patients with damaged blood vessels using adult bone marrow-derived stem cells. Endothelial cells line the blood vessels and can be injured during chronic diabetes. We recently demonstrated that an important normal regulator of bone marrow-derived stem cells is TGF-21 but overproduction can naturally slow vessel repair by stem cells through a negative regulatory pathway. Here we hypothesize that blocking the gene expression of TGF-21 in human HSC will accelerate vascular repair, especially after heart attacks. Importantly, we recently showed that HSC from diabetic patients are defective in their ability to repair damaged vessels compared to normal individuals. Furthermore, other studies have now shown that African- Americans with diabetes can have high levels of TGF-21, which can exacerbate their diabetic vascular damage. Our focus is to demonstrate proof of principle that adult HSC can be effectively used to repair infarcted coronary vessels and eventually greatly improve the quality and duration of these patient's lives.
Public Health Relevance Statement: Lay Abstract: This research proposal aims to treat diabetic patients with damaged blood vessels using adult bone marrow-derived stem cells. Endothelial cells line the blood vessels and can be injured during chronic diabetes. We recently demonstrated that an important normal regulator of bone marrow-derived stem cells is TGF-¿1 but overproduction can naturally slow vessel repair by stem cells through a negative regulatory pathway. Here we hypothesize that blocking the gene expression of TGF-¿1 in human HSC will accelerate vascular repair, especially after heart attacks. Importantly, we recently showed that HSC from diabetic patients are defective in their ability to repair damaged vessels compared to normal individuals. Furthermore, other studies have now shown that African- Americans with diabetes can have high levels of TGF-¿1, which can exacerbate their diabetic vascular damage. Our focus is to demonstrate proof of principle that adult HSC can be effectively used to repair infarcted coronary vessels and eventuallygreatly improve the quality and duration of these patients lives.
Project Terms: 21+ years old; Adherence; Adherence (attribute); Adoptive Transfer; Adult; African American; Afro American; Afroamerican; Age; Area; Autologous; Black Populations; Black or African American; Blood Precursor Cell; Blood Serum; Blood Vessels; Blood capillaries; Body Tissues; Bone Marrow; Bone-Derived Transforming Growth Factor; C-X-C Chemokine Receptor Type 4; CD184 Antigen; CD34; CD34 gene; CXC-R4; CXCR-4; CXCR4; CXCR4 Receptors; CXCR4 gene; Capillaries; Capillary; Capillary, Unspecified; Cardiac; Cardiac infarction; Caucasian; Caucasian Race; Caucasians; Caucasoid; Caucasoid Race; Cell Function; Cell Line; Cell Lines, Strains; Cell Process; Cell physiology; CellLine; Cells; Cellular Function; Cellular Physiology; Cellular Process; Chemoattractants; Chemokine (C-X-C Motif) Receptor 4; Chemokine, CXC Motif, Receptor 4; Chemotactic Factors; Chemotaxins; Chemotaxis; Chronic; Clinical; Clinical Trials; Clinical Trials, Unspecified; Coronary Vessels; Cytokines, Chemotactic; D2S201E; Data; Defect; Diabetes Mellitus; Diabetes Mellitus, Adult-Onset; Diabetes Mellitus, Ketosis-Resistant; Diabetes Mellitus, Non-Insulin-Dependent; Diabetes Mellitus, Noninsulin Dependent; Diabetes Mellitus, Slow-Onset; Diabetes Mellitus, Stable; Diabetes Mellitus, Type 2; Diabetes Mellitus, Type II; Dysfunction; Endothelial Cells; Engraftment; FB22; Florida; Functional disorder; Fusin; Gene Expression; Generalized Growth; Grant; Growth; HM89; HPCA1; HSY3RR; Heart; Hematopoietic stem cells; Homing; Homologous Chemotactic Cytokines; Human; Human, Adult; Human, General; Individual; Infarction; Injury; Intercrines; Ischemia; LAP3; LCR1; LESTR; LPS-Associated Protein 3; Laboratories; Lead; Legal patent; Leukocyte-Derived Seven-Transmembrane Domain Receptor; Life; Lipopolysaccharide-Associated Protein 3; MODY; Mammals, Mice; Man (Taxonomy); Man, Modern; Maturity-Onset Diabetes Mellitus; Mechanics; Mediating; Methods and Techniques; Methods, Other; Mice; Milk Growth Factor; Modeling; Molecular; Mother Cells; Murine; Mus; Myocardial Infarct; Myocardial Infarction; NIDDM; NPY3R; NPYR; NPYRL; NPYY3R; Neuropeptide Y Receptor Y3; Non-Insulin Dependent Diabetes; Non-Insulin-Dependent Diabetes Mellitus; Nude Rats; Occidental; PMO oligomer; Patents; Patients; Pb element; Pharmacology; Phase; Physiopathology; Platelet Transforming Growth Factor; Population; Populations at Risk; Progenitor Cells; Progenitor Cells, Hematopoietic; Rats, Athymic; Rats, Nude; Receptor Protein; Receptor, LESTR; Regulatory Pathway; Research; Research Proposals; Reticuloendothelial System, Bone Marrow; Risk; SDF-1 Receptor; SDF1/PBSF Receptor CXCR4; SIS cytokines; Series; Serum; Seven-Transmembrane-Segment Receptor, Spleen; Site; Stem cells; Stents; Stromal Cell-Derived Factor 1 Receptor; Subcellular Process; T2D; T2DM; TGF B; TGF-beta; TGFbeta; Techniques; Testing; Therapeutic; Tissue Growth; Tissues; Transforming Growth Factor beta; Tube; Type 2 diabetes; Type II diabetes; Universities; abstracting; adult human (21+); adult onset diabetes; base; black American; capillary; cardiac infarct; cardiovascular disease risk; cardiovascular disorder risk; chemoattractant cytokine; chemokine; clinical investigation; clinical significance; clinically significant; complement chemotactic factor; coronary attack; coronary infarct; coronary infarction; cultured cell line; diabetes; diabetic; diabetic patient; heart attack; heart infarct; heart infarction; heavy metal Pb; heavy metal lead; improved; in vitro Assay; infarct; injured; ketosis resistant diabetes; maturity onset diabetes; non-diabetic; nondiabetic; novel; ontogeny; paracrine; pathophysiology; phosphorodiamidate morpholino oligomer; precursor cell; public health relevance; receptor; reconstitute; reconstitution; repair; repaired; response; senescence; vascular; white race
