Ivan Maillard , M.D., Ph.D.
Assistant Professor
Internal Medicine

imaillar@umich.edu

Research Interests:

Hematopoietic stem cells, fetal hematopoiesis, T cell differentiation, Notch signaling

Research Activity:

Research in the laboratory will be devoted to the following main topics: 1) investigating the interaction of hematopoietic stem cells (HSC) with their microenvironmental niche, particularly in fetal sites of hematopoiesis, and 2) understanding the role of Notch signaling in the regulation of T cell homeostasis and differentiation.

We have previously investigated the role of Notch signaling, a highly conserved cell-cell communication pathway, in the regulation of HSC homeostasis and at early stages of T cell development. Using a potent and specific dominant negative inhibitor (DNMAML) to block Notch-mediated transcriptional activation, we found that canonical Notch signaling is dispensable for the homeostasis of adult HSCs, but absolutely required at the earliest stages of T cell development. In contrast, disruption of Notch signaling during mid-gestation led to dysregulation of the HSC pool in the fetal liver, with evidence of initial activation followed by loss of long-term HSCs. Importantly, these effects were mediated by a non-cell autonomous effect of DNMAML on the microenvironment, and not by loss of Notch signaling in hematopoietic progenitors. DNMAML expression resulted in disruption of microvascular elements in the fetal liver. On the basis of these results, we hypothesize that microvascular structures are an essential component of the HSC niche in fetal tissues, and we postulate that the integrity and function of the microvascular endothelium are regulated by Notch signaling. To investigate this hypothesis, we propose to study the interaction of fetal HSCs and microvascular structures using a combination of genetic and cellular approaches. Our ultimate goal is to identify the critical elements of the HSC niche in fetal tissues.

In addition, we are interested in the regulation of mature T cell homeostasis and differentiation by Notch signaling. Using the DNMAML system in collaboration with Dr Y. Zhang, we are investigating the molecular and cellular mechanisms underlying the activity of Notch signaling in different types of T cell responses.

Representative Recent Publications:

1. I. Maillard and W.S. Pear. Keeping a tight leash on Notch. Science, 316:840-842, 2007.

2. Zediak V.P., I. Maillard and A. Bhandoola. Multiple pre-thymic defects underlie age-related loss of T progenitor competence. Blood , epub ahead of print, 2007.

3. L. Talebian, Z. Li, Y. Guo, J. Gaudet, M.E. Speck, D. Sugiyama, P. Kaur, W.S. Pear, I. Maillard * and N.A. Speck*. T lymphoid, megacaryocyte, and granulocyte development are sensitive to decreases in CBFbeta dosage. Blood (Plenary paper) , 109(1):11-21, 2007 (* corresponding authors ).

4. Maillard I. , L. Tu, A. Sambandam, Y. Yashiro-Ohtani, J. Millholland, K. Keeshan, O. Shestova, L. Xu, A. Bhandoola and W.S. Pear. The requirement for Notch signaling at the beta selection checkpoint in vivo is absolute and independent of the pre-T cell receptor. J. Exp. Med. , 203(10): 2239-45, 2006.

5. Maillard I. , B. Schwarz, A. Sambandam, T.Fang, O. Shestova, L. Xu, A. Bhandoola and W.S. Pear. Notch-dependent T lineage commitment occurs at extrathymic sites following bone marrow transplantation. Blood , 107(9): 3511-19, 2006.

6. Tu L., T.C. Fang, D. Artis, O. Shestova, S.E. Pross, I. Maillard and W.S. Pear.Notch signaling is an important regulator of type 2 immunity. J. Exp. Med. , 202(8):1037-42, 2005.

7. Maillard I. , T. Fang and W.S. Pear. Regulation of lymphoid development, differentiation and function by the Notch pathway. Annu Rev Immunol , 23:945-974, 2005.

8. Sambandam A.*, I. Maillard *, V.P. Zediak, L. Xu, R.M. Gerstein, J.C. Aster, W.S. Pear and A. Bhandoola. N otch signaling controls the generation and differentiation of early T lineage progenitors. Nature Immunology , 6(7):663-70, 2005 (* equal contribution ).

9. Maillard I. , A.P. Weng, A.C. Carpenter, C.G. Rodriguez, H. Sai, L. Xu, D. Allman, J.C. Aster, and W.S. Pear. Mastermind critically regulates Notch-mediated lymphoid cell fate decisions. Blood , 104(6):1696-702, 2004.