Partha Dutta, DVM, PhD
Campus: 200 Lothrop Street
Office: BST 1720.1
Pittsburgh, PA 15261
- B.V.Sc & A.H- West Bengal University of Animal and Fishery Sciences, India, 2003
- MS- Wichita State University, KS, USA, 2006
- PhD- University of Wisconsin-Madison, WI, USA, 2010
- Postdoctoral training- Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, 2013
- Instructor- Harvard Medical School, 2015
- Assistant Professor of Medicine
Role of inflammation in cardiovascular diseases
Cardiovascular disease is the leading cause of death in developed countries. Inflammation aggravates outcome of cardiovascular disease including atherosclerosis and infarct healing after myocardial infarction (MI) (Leuschner* and Dutta* et al., Nature Biotechnology, 2011). During progression of atherosclerosis, myeloid cells destabilize lipid-rich plaques in the arterial wall and cause their rupture, thus triggering myocardial infarction and stroke. Survivors of acute coronary syndromes have a high risk of recurrent events for unknown reasons. We showed that the systemic response to ischemic injury aggravates chronic atherosclerosis (Dutta et al., Nature, 2012). After myocardial infarction or stroke, Apoe-/- mice developed larger atherosclerotic lesions with a more advanced morphology and inflammation (Figure 1). This disease acceleration persisted over many weeks and was associated with markedly increased monocyte recruitment.
Figure 1: Increased inflammation in the aortic root measure by FMT-CT imaging (Dutta et al., Nature, 2012)
Activation of hematopoietic stem cells after myocardial infarction:
Hematopoietic stem cells get activated after acute or chronic inflammation and give rise to exaggerated myelopoiesis (Figure 2).
Fig. 2: Schematic diagram depicting possible mechanism of how bone marrow HSC can influence healing of the myocardium after MI (Dutta et al., Cell Stem Cell, 2015).
However, most hematopoietic stem cells (HSC) are quiescent, and it is currently unknown whether they respond to ischemic organ injury. We identified a CCR2+ HSC subset, which has fourfold higher proliferative rate than CCR2- HSC, as the most upstream contributor to myelopoiesis after myocardial infarction (Figure 3) (Dutta et al., Cell Stem Cell, 2015). CCR2+ HSC display bias towards the myeloid lineage and dominate the migratory HSC population after myocardial infarction and in steady-state. The myeloid translocation gene 16 (Mtg16) regulates the emergence of CCR2+ HSC from CCR2- HSC. These data shed new light on the regulation of emergency hematopoiesis after ischemic injury and identify novel therapeutic targets to modulate leukocyte output after myocardial infarction.
Fig. 3: Flow cytometric gating strategy for CCR2+ HSC and proliferation of the HSC subsets after myocardial infarction (Dutta et al., Cell Stem Cell, 2015).
Additionally, we found that myocardial infarction drives splenic hematopoietic stem cells into the cell cycle resulting in production of myeloid cells at the extramedullary site (Dutta et al., Journal of Experimental Medicine, 2015). Moreover, splenic HSC are retained by VCAM-1+ splenic macrophages (Figure 4).
Fig. 4: Interaction between splenic macrophages (red) and hematopoietic stem cells (green) (Dutta et al., Journal of Experimental Medicine, 2015).
- Dutta P, Sager H, Stengel K, Naxerova K,……Libby P, Hiebert S, Scadden D, Swirski FK, Weissleder R, Nahrendorf M. 2015. Myocardial infarction activates CCR2+ hematopoietic stem cells. Cell Stem Cell 16: 477-87.
- Dutta, P., F. F. Hoyer, L. S. Grigoryeva, H. B. Sager, F. Leuschner, G. Courties, A. Borodovsky, T. Novobrantseva, V. M. Ruda, K. Fitzgerald, Y. Iwamoto, G. Wojtkiewicz, Y. Sun, N. Da Silva, P. Libby, D. G. Anderson, F. K. Swirski, R. Weissleder, and M. Nahrendorf. 2015. Macrophages retain hematopoietic stem cells in the spleen via VCAM-1 in atherosclerosis. Journal of Experimental Medicine 212: 497-512.
- Sager HB, T. Heidt, M. Hulsmans, P. Dutta, G. Courties, M. Sebas, G. R. Wojtkiesicz, B. Tricot, Y. Iwamoto, Y. Sun, R. Weissleder, P. Libby, F.K. Swirski, M. Nahrendorf. 2015. Targeting interleukin-1beta reduces leukocyte production after acute myocardial infarction. Circulation.
- Dutta, P., G. Courties, Y. Wei, F. Leuschner, R. Gorbatov, C. S. Robbins, Y. Iwamoto, B. Thompson, A. L. Carlson, T. Heidt, M. D. Majmudar, F. Lasitschka, M. Etzrodt, P. Waterman, M. T. Waring, A. T. Chicoine, A. M. van der Laan, H. W. Niessen, J. J. Piek, B. B. Rubin, J. Butany, J. R. Stone, H. A. Katus, S. A. Murphy, D. A. Morrow, M. S. Sabatine, C. Vinegoni, M. A. Moskowitz, M. J. Pittet, P. Libby, C. P. Lin, F. K. Swirski, R. Weissleder, and M. Nahrendorf. 2012. Myocardial infarction accelerates atherosclerosis. Nature 487: 325-329.
- Heidt, T., H. B. Sager, G. Courties, P. Dutta, Y. Iwamoto, A. Zaltsman, C. von Zur Muhlen, C. Bode, G. L. Fricchione, J. Denninger, C. P. Lin, C. Vinegoni, P. Libby, F. K. Swirski, R. Weissleder, and M. Nahrendorf. 2014. Chronic variable stress activates hematopoietic stem cells. Nature Medicine 20: 754-758.
- Leuschner, F*., P. Dutta*, R. Gorbatov, T. I. Novobrantseva, J. S. Donahoe, G. Courties, K. M. Lee, J. I. Kim, J. F. Markmann, B. Marinelli, P. Panizzi, W. W. Lee, Y. Iwamoto, S. Milstein, H. Epstein-Barash, W. Cantley, J. Wong, V. Cortez-Retamozo, A. Newton, K. Love, P. Libby, M. J. Pittet, F. K. Swirski, V. Koteliansky, R. Langer, R. Weissleder, D. G. Anderson, and M. Nahrendorf. 2011. Therapeutic siRNA silencing in inflammatory monocytes in mice. Nature Biotechnology 29: 1005-1010. * Equal contribution authors
- Dutta, P., M. Dart, D. A. Roenneburg, J. R. Torrealba, and W. J. Burlingham. 2011. Pretransplant immune-regulation predicts allograft tolerance. Am J Transplant 11: 1296-1301.
- Dutta, P., M. Molitor-Dart, J. L. Bobadilla, D. A. Roenneburg, Z. Yan, J. R. Torrealba, and W. J. Burlingham. 2009. Microchimerism is strongly correlated with tolerance to noninherited maternal antigens in mice. Blood 114: 3578-3587.
Click here for full list of publications
- Role of inflammation in cardiovascular diseases
- Activation of hematopoietic stem cells after myocardial infarction