Last Updated: 2/19/2009

Research Interests
Role of Wnt signaling in determining stem cell choices of self-renewal versus differentiation
A major area of interest in our laboratory is to understand molecular signals that determine the fate of tissue specific adult stem cells i.e. whether to self renew or differentiate into the target cell of choice. We have focused on the Wnt signaling system to study this process both in vivo and in vitro both in embryonic and tissue specific stem cells isolated from solid organs such as the heart. Wnts are a family of 20 lipid-modified proteins that exert diverse cellular effects including proliferation, apoptosis and differentiation. In fact unchecked Wnt signaling leads to uncontrolled cell proliferation and has been implicated in several human cancers such as of the breast, colon and esophagus. Similarly, epigenetic silencing of Wnt inhibitors such as Sfrp (secreted related frizzled protein) leads to uncontrolled Wnt signaling, cell proliferation and is observed in human bladder cancers. There is mounting evidence in the literature that points to cancer being a stem cell disease; i.e. accumulated mutations or abnormal signaling drives a stem cell to proliferate abnormally and leads to a progeny of cells with the same abnormal phenotype. Such abnormal events are ultimately precipitated by signaling changes that irreversibly alter the balance between self-renewal and proliferation versus differentiation. Studying signaling systems that regulate such diverse fates in stem cells are of obvious clinical importance as alteration of abnormal signaling through pharmacologic or genetic means may be beneficial for cancer therapy.

In this regard, we have recently demonstrated that Sfrp2, an extracellular Wnt antagonist serves as a checkpoint gene that regulates differentiation versus self-renewal of embryonic stem cells (Deb et al Stem Cells 2008). When induced to differentiate, murine embryonic stem cells expressed canonical Wnts that increased the degree of differentiation of these stem cells. Moreover canonical Wnts exerted a positive feedback loop on its own expression and led to a near exponential increase in the expression of Wnts in differentiating embryonic stem cells. This system was balanced by the expression of Sfrp2 that bound Wnts extracellularly, interrupted this feedback effect and regulated differentiation. Using gain and loss of function approaches, we showed that Sfrp2 critically regulated this process; overexpression of Sfrp2 inhibited stem cell differentiation while inhibition of Sfrp2 drove differentiation and inhibited cell proliferation. These insights shed some light on some of the molecular signals that regulate regulate stem cell differentiation, proliferation and self-renewal. We have recently extended these observations to show that similar mechanisms appear to regulate differentiation and self-renewal of adult tissue specific stem cells. We isolated cardiac stem cells from the adult heart and observed that Wnts commit adult cardiac stem cells to differentiate while Sfrp2 appears to inhibit differentiation, promotes proliferation and maintains stemness. Our laboratory is currently pursuing these observations and investigating in depth the signaling mechanisms in adult tissues (liver and heart) that maintain a balance between proliferation and self-renewal versus differentiation of stem cells. (This project is currently supported by NIH R00HL088317).

Role of stem cells in regulating aging of solid organs
A second major focus of our laboratory is to understand molecular changes that underlie age related decline of physiological function in solid organs. Although hematopoietic stem cell function has been studied extensively, the physiological function of stem cells of solid organs in the adult remains unclear. In particular whether stem cells undergo senescence and stop self-renewal as the organ ages is not clear. Similarly whether age related increase in fibrosis in many solid organs such as the heart and liver is secondary to decreased/aberrant stem cell differentiation remains a critically important but unanswered question. Senescence has been traditionally thought of as an anti-neoplastic mechanism to curb the development of tumors with age. However these powerful anti-tumor mechanisms may also underlie age related decline in stem cell number and function. It thus appears that a physiological decline in stem cell pools is a trade off for preventing new tumor development. What then are the molecular signals that promote senescence in stem cell pools in solid organs such as the heart and liver? Does increased fibrosis or fatty changes seen in the heart and liver with age secondary to aberrant differentiation of tissue specific stem cells in these organs? Are molecular signals driving senescence and aberrant differentiation related in any manner?

To answer these questions, we have chosen to study signaling mechanisms of stem cells isolated from young and old rodent hearts and livers. Preliminary data generated in our laboratory points to the Wnt signaling system driving aberrant differentiation of cardiac stem cells into fibroblasts rather than cardiomyocytes. We also observe an age related increase in downstream Wnt signaling. These observations although preliminary, suggest that an age related increase in aberrant differentiation, and not senescence, may explain decreasing stem cell pools in older organs. We also noted that inhibition of Wnt signaling appeared to prevent aberrant differentiation and preserved stem cell pools. This is a new area of investigation in our laboratory and we have been fortunate to have received funding from the Ellison Medical Foundation for Aging for this proposal. Our main goals are to determine whether alteration of Wnt signaling can prevent aberrant differentiation, and preserve stem cell pools in the heart and liver without increasing the incidence of solid tumors in aging animals.

Recent Accomplishments and Honors
2008 Ellison medical Foundation New Scholar in Aging
2006 National Institute of Health Pathway to Independence program award
2006 American Heart Association Post doctoral fellowship award (Atlantic affiliate)
2006 GSK Research & Education Foundation for Cardiovascular Disease Young Investigator International Competitive Grant Award
2004 Bristol Myers Squibb/ACC Travel Award, American College of Cardiology,Orlando
2003 Young Investigator Award, American College of Cardiology, Scientific sessions, Chicago
2003 Mayo Foundation Outstanding Achievement Award for excellence in Internal Medicine Residency
2001 National Medical jeopardy Contest (2nd position), American College of Physicians Meeting, Atlanta
2000 Winner, Regional Medical Jeopardy Contest, American College of Physicians Meeting, Minneapolis
2000 Winner, National Medical Jeopardy Contest at American College of Physicians Meeting, Philadelphia
1999 Winner, Regional Medical Jeopardy Contest at American College of Physicians Meeting, Minneapolis

Training
Calcutta Medical College, University of Calcutta, India M.B.B.S (10/1997) 1991-1997 Medical School
Mayo Clinic College of Medicine, Rochester, MN Diplomate, ABIM 1999-2002 Internal medicine (Residency)
Mayo Clinic College of Medicine, Rochester, MN Diplomate, ABIM/CV Diseases 2002-2005 Cardiovascular Diseases (Fellowship, Clinical & Research)
Duke University Medical Center, Durham, NC 2005-2007 Cardiovascular & Stem Cell biology (Post doctoral fellowship)

Publications
1. Mirotsou M, Zhnag Z, Deb A, Zhang L, Gneechi M, Noiseux N, Mu H, Pachori A, Dzau V. Sfrp2 mediates the paracrine survival signal of Akt genetically modified mesenchymal stem cell for myocardial protection and repair. Proc Natl Acad Sci U.S.A 2007 104(5):1643-8
2. Deb A, Guo J, Ni A, Davis B, Huang J, Zhang J, Mu H, Dzau V J. SFRP2 regulates cardiomyogenic differentiation by inhibiting a positive transcriptional auto-feedback loop of Wnt3a. Stem Cells, 2008;26(1) 35-44

E-mail: arjundeb@med.unc.edu
Telephone: 919-843-8376
FAX: 919-966-6012
Address: 3212B MBRB Chapel Hill, NC 27599

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