Sergio Li Calzi, M.S., Ph.D.
Senior Research Scientist
Combination Stem Cell Therapy for Myocardial Regeneration
Despite recent advances in medical therapy, ischemic heart disease remains one of the leading causes of morbidity and mortality worldwide. Stem cells therapy aimed to cardiac tissue regeneration may be a valuable therapeutic option.
Adult bone marrow contains a reservoir of cells with plasticity. Animal studies and, more importantly, clinical trials have supported the use of bone marrow-derived stem cells (BMSCs) to repair the heart. Collectively, these studies have demonstrated the safety and feasibility of cell therapy for cardiovascular disease. However, in all published cell therapy clinical trials to date, cohorts of patients who have received stem cell injections have failed to show a response in ejection fraction, a measure of global left ventricular function. Thus there remains a critical need to optimize cell therapy technology.
One of the main limitations of stem cell studies is a low survival rate of transplanted cells, affected by inflammatory molecules, proapoptotic factors, and lack of nutrients and oxygen.
Since myocardial infarction (MI) results in irreversible damage to the left ventricular wall leading to remodeling and dysfunction, development of treatments aimed to regenerate the muscular tissue and vascular network is now considered a main therapeutic challenge. Unfortunately, the human heart has a very limited ability to regenerate function after injury. This reality has garnered enthusiasm for supplying damaged hearts with healthy, functional cells to repair or replace diseased ones.
We hypothesized that using cardiac stem cells (CSC) in combination with bone marrow –derived stem cells (BMSC) will provide additive or even synergistic myocardial repair following injury. Exogenous BMSC will enhance vascular regeneration by direct contribution to cardiac capillary formation or as paracrine regulators of blood vessel growth while exogenous Isl-1+ CSC will foster cardiomyocyte regeneration.
Our hypothesis predicts that myocardial function would be enhanced by combination stem cell therapy. Angiogenesis in the myocardium, enhanced using Thy-1+ cells (rat precursor cells equivalent to human CD34+ cells), would facilitate CSC survival and proliferation. The model system we use is the rat model of myocardial infarction (MI) induced by left anterior descending (LAD) artery ligation. We tested our hypothesis by simultaneously injecting BMSC and CSC at the time of LAD ligation and evaluated myocardial repair by in vivo hemodynamic measurements followed by histological examination. The results were compared to stem cell monotherapies and untreated animals. This study is in its final stages and will soon be submitted for publication (Figure 1, 2).
Dr. Li Calzi is a member of the Grant Lab (Maria Grant, M.D., FARVO).
- American Heart Association - Beginning Grant-in-Aid.
Novel Combination Therapy for Myocardial Repair.
Period 1 Start Date: 07/01/2008, End Date: 06/30/2009
Period 2 Start Date: 07/01/2009, End Date: 06/30/2010
Period 3 Start Date: 07/01/2010, End Date: 06/30/2011
- American Heart Association - Postdoctoral Fellowship.
MRI as a Novel Non-invasive Method for in vivo Tracking of EPCs in Myocardial Dysfunction
in Diabetic Mice.
Period 1 Start Date: 07/01/2006, End Date: 06/30/2007
Period 2 Start Date: 07/01/2007, End Date: 06/30/2008
(Selected publications from 34)
- Yan Y, Salazar TE, Dominguez JM 2nd, Nguyen DV, Li Calzi S, Bhatwadekar AD, Qi X, Busik JV, Boulton ME, Grant MB. Dicer Expression Exhibits a Tissue-Specific Diurnal Pattern That Is Lost during Aging and in Diabetes. PLoS One. 2013 Nov 7;8(11):e80029. doi: 10.1371/journal.pone.0080029. PMID: 2424459
- Caballero S, Hazra S, Bhatwadekar A, Li Calzi S, Paradiso LJ, Miller LP, Chang LJ, Kern TS, Grant MB. Circulating Mononuclear Progenitor Cells: Differential Roles for Sub-populations in Repair of Retinal Vascular Injury. Invest Ophthalmol Vis Sci. 2013 Apr 9. doi:pii: iovs.12-10280v1. 10.1167/iovs.12-10280. PMID: 23572102
- Tikhonenko M, Lydic TA, Opreanu M, Li Calzi S, Bozack S, McSorley KM, Sochacki AL, Faber MS, Hazra S, Duclos S, Guberski D, Reid GE, Grant MB, Busik JV. N-3 polyunsaturated Fatty acids prevent diabetic retinopathy by inhibition of retinal vascular damage and enhanced endothelial progenitor cell reparative function. PLoS One. 2013;8(1):e55177. doi: 10.1371/journal.pone.0055177. Epub 2013 Jan 29. PMID: 23383097
- Hazra S, Jarajapu YP, Stepps V, Caballero S, Thinschmidt JS, Sautina L, Bengtsson N, Li Calzi S, Dominguez J, Kern TS, Segal MS, Ash JD, Saban DR, Bartelmez SH, Grant MB. Long-term type 1 diabetes influences haematopoietic stem cells by reducing vascular repair potential and increasing inflammatory monocyte generation in a murine model. Diabetologia. 2013 Mar;56(3):644-53. doi: 10.1007/s00125-012-2781-0. Epub 2012 Nov 29. PMID: 23192694
- Bhatwadekar AD, Yan Y, Qi X, Thinschmidt JS, Neu MB, Li Calzi S, Shaw LC, Dominiguez JM, Busik JV, Lee C, Boulton ME, Grant MB. Per2 Mutation Recapitulates the Vascular Phenotype of Diabetes in the Retina and Bone Marrow. Diabetes. 2012 Nov 27. [Epub ahead of print] PMID: 23193187
- Ma L, Li N, Liu X, Shaw L, Li Calzi S, Grant MB, Neu J. Arginyl-glutamine dipeptide or docosahexaenoic acid attenuate hyperoxia-induced lung injury in neonatal mice. Nutrition. 2012 Nov;28(11-12):1186-91. PMID: 23044165
- Jarajapu YPR, Cai J, Yan Y, Li Calzi S, Kielczewski JL, Hu P, Shaw LC, Firth SM, Chan-Ling T, Boulton ME, Baxter RC and Grant MB. Innate Protection of Blood Retinal Barrier and Systemic Vasculature by Insulin-Like Growth Factor Binding Protein-3. PLoS One. 2012;7(7):e39398. Epub 2012 Jul 6. PMID: 22792172
- Yellowlees-Douglas J, Bhatwadekar AD, Li Calzi S, Shaw LC, Carnegie D, Caballero S, Li Q, Stitt AW, Raizada MK, Grant MB. Bone marrow-CNS connections: Implications in the pathogenesis of diabetic retinopathy. Prog Retin Eye Res. 2012 Sep;31(5):481-94. Epub 2012 May 15. PMID: 22609081
- Li N, Ma L, Liu X, Shaw L, Li Calzi S, Grant M, Neu J. Arginyl-Glutamine (Arg-Gln) Dipeptide or Docosahexaenoic Acid (DHA) Attenuate Hyperoxia-Induced Small Intestinal Injury in Neonatal Mice. J Pediatr Gastroenterol Nutr. 2011 Oct 20. [Epub ahead of print] PMID: 22020559
- Kielczewski JL, Li Calzi S, Shaw LC, Cai J, Qi X, Ruan Q, Wu L, Liu L, Hu P, Chan-Ling T, Mames RN, Firth S, Baxter RC, Turowski P, Busik JV, Boulton ME, and Grant MB Free Insulin-like Growth Factor Binding Protein-3 (IGFBP-3) reduces retinal vascular permeability in association with a reduction of acid sphingomyelinase (ASMase) Invest Ophthalmol Vis Sci. 2011 Sep 19. [Epub ahead of print]
- Cai J, Wu L, Qi X, Li Calzi S, Caballero S, Shaw LC, Ruan Q, Grant MB, Boulton ME. PEDF regulates vascular permeability by a ?-secretase-mediated pathway. PLoS One. 2011;6(6):e21164. Epub 2011 Jun 17.
- Cai J, Wu L, Qi X, Shaw L, Li Calzi S, Caballero S, Jiang WG, Vinores SA, Antonetti D, Ahmed A, Grant MB, Boulton ME. Placenta Growth Factor-1 Exerts Time-Dependent Stabilization of Adherens Junctions Following VEGF-Induced Vascular Permeability. PLoS One. 2011 Mar 25;6(3):e18076. [PMID: 21464949]
- Kielczewski JL, Hu P, Shaw LC, Li Calzi S, Mames RN, Gardiner TA, McFarland E, Chan-Ling T, Grant MB. Novel protective properties of IGFBP-3 result in enhanced pericyte ensheathment, reduced microglial activation, increased microglial apoptosis, and neuronal protection after ischemic retinal injury. Am J Pathol. 2011 Apr;178(4):1517-28. [PMID: 21435441]
- Busik JV, Tikhonenko M, Bhatwadekar A, Opreanu M, Yakubova N, Caballero S, Player D, Nakagawa T, Afzal A, Kielczewski J, Sochacki A, Hasty S, Li Calzi S, Kim S, Duclas SK, Segal MS, Guberski DL, Esselman WJ, Boulton ME, Grant MB. Diabetic retinopathy is associated with bone marrow neuropathy and a depressed peripheral clock. J Exp Med. 2009 Nov 23.
- Kielczewski, J.L., Jarajapu, Y., McFarland, E.L., Cai, J., Afzal, A., Li Calzi, S., Chang, KH., Lydic, T., Shaw, L.C., Busik, J., Hughes, J., Cardounel, A.J., Wilson, K., Lyons, T.J., Boulton, M.E., Mames, R.N., Chan-Ling, T. and Grant, M.B. Insulin-like Growth Factor Binding Protein-3 Mediates Vascular Repair by Enhancing Nitric Oxide Generation. Circ Res. 2009 Sep 17.
- Sengupta, N., Caballero, S., Sullivan, S.M., Chang, LJ., Afzal, A., Li Calzi, S., Kielczewski JL, Prabarakan S, Ellis EA, Moldovan L, Moldovan NI, Boulton ME, Grant MB. Regulation of adult hematopoietic stem cells fate for enhanced tissue-specific repair. Mol Ther. 2009 Sep;17(9):1594-604. Epub 2009 Jul 7.
- Li Calzi, S., Kent , D.L., Chang, K-H., Chandra, S., Padgett, K., Afzal, A., Caballero, S., Garlington, W., Hiscott, P., Sheridan, C., Grant M.B., and Forder, J.R., Monocrystalline Iron Oxide Nanoparticles for Labeling Human Endothelial Progenitor Cells for MRI. Microvasc Res. 2009 Jun;78(1):132-9. Epub 2009 Apr 5.
- Kramerov, A.A., Saghizadeh, M., Caballero, S., Shaw, L.C., Li Calzi, S., Bretner, M., Montenarh, M., Pinna, L.A., Grant, M.B., Ljubimov, A.V. Inhibition of protein kinase CK2 suppresses angiogenesis and hematopoietic stem cell recruitment to retinal neovascularization sites. Mol Cell Biochem 2008 Sep;316(1-2):177-86.
- Li Calzi, S., Purich, D.L., Chang, K-H., Afzal, A., Nakagawa, T., Agarwal, A., Busik, J.V. Segal, M.C., and Grant, M.B. Carbon Monoxide and Nitric Oxide Mediate Cytoskeletal Reorganization in Microvascular Cells via Vasodilator-Stimulated Phosphoprotein (VASP) Phosphorylation: Evidence for Blunted Responsiveness in Diabetes. Diabetes 2008 Sep;57(9):2488-94.
- Chang, K-H., Chan-Ling, T., McFarland, E.L., Afzal, A., Pan, H., Baxter, L.C., Shaw, L.C., Caballero, S., Sengupta, N., Li Calzi, S., Sullivan, S.M. and Grant, M.B. IGF Binding Protein-3 Regulates Hematopoietic Stem Cell and Endothelial Precursor Cell Function During Vascular Development. Proc Natl Acad Sci U S A. 2007 Jun 19;104(25):10595-600.
- Caballero, S., Sengupta, N., Afzal, A., Chang, K-H., Li Calzi, S., Guberski, D.L., Kern, T.S., and Grant, M.B. Ischemic Vascular Damage Can Be Repaired by Healthy, but Not Diabetic, Endothelial Progenitor Cells. Diabetes 2007, 56: 960-967.
- Deshane, J., Chen, S., Caballero, S., Grochot-Przeczek, A., Was, H., Li Calzi, S., Lach, R., Hock, T.D., Chen, B., Hill-Kapturczak, N., Siegal, G.P., Dulak, J., Jozkowicz, A., Grant, M.B., and Agarwal, A. Stromal cell-derived factor-1 promotes angiogenesis via a heme oxygenase 1- dependent mechanism. Journal of Experimental Medicine 2007, Mar 19; 204(3): 605-18.
- Yu, R., Cruz-Soto, M., Li Calzi, S., Hongxiang, H., and Melmed, S. Murine PTTG functions as a securin protein in insulin-secreting cells. Journal of Endocrinology 2006, 191: 45–53.
- Neu, J., Afzal, A., Pan, H., Gallego, E., Li, N., Li Calzi, S., Caballero, S., Spoerri, P.E., Shaw, L.C., and Grant, M.B. The Dipeptide Arg-Gln Inhibits Retinal Neovascularization in the Mouse Model of Oxygen Induced Retinopathy. IOVS Jul. 2006, 47(7): 3151-3155.
- Shaw, L.C., Pan, H., Afzal, A., Li Calzi, S., Spoerri, P.E., Sullivan, S.M., and Grant, M.B. Proliferating endothelial cell-specific expression of IGF-I receptor ribozyme inhibits retinal neovascularization. Gene Therapy 2006, May;13(9): 752-760.
- Ph.D. - Medical College of Ohio, Toledo, OH
- M.S. - University of Messina, Messina, Italy
- Postdoctoral training - University of Florida, Gainesville, FL
- Postdoctoral training - Cedars-Sinai Medical Center, Los Angeles, CA
- Board Exam for Biologists - University of Messina, Messina, Italy
- 2005 - Present - Metabolism – Clinical and Experimental.
- 2007 - Present - Investigative Ophthalmology and Visual Science (IOVS)
- 2013 - PLoS One
- 1997 Honorable Mention - 12th Annual Graduate Student Research Forum, Medical College of Ohio, Toledo, OH.
- 2010 EPMA Journal Awarded Article Li Calzi S. et al. [PMID:21494317]