Boston Children's Hospital
Warren Alpert Building, Room 149i
200 Longwood Ave.
Boston, MA 02115
The unique ability of stem cells to perpetuate themselves through self-renewal, and to give rise to mature effector cell types in a sustained fashion has positioned stem cell biology at the forefront of regenerative medicine -- the goal of which is to develop strategies capable of harnessing the clinical potential of stem cells to treat both heritable and acquired degenerative conditions. Hematopoietic stem cells (HSCs) are the only cells within the bone marrow that possess the ability to both differentiate to all blood lineages, and to self-renew for life. These properties, along with the remarkable ability of HSCs to engraft conditioned recipients upon intravenous transplantation, have established the clinical paradigm for stem cell use in regenerative medicine. Despite the enormous clinical potential of HSCs, surprisingly little is known about the mechanisms that regulate their fundamental properties of self-renewal and multi-potency. Our lab has a profound interest in understanding the mechanisms enabling self-renewal and multi-potency in HSCs, which we study using cellular, molecular, genetic and epigenetic approaches.
Our lab is also interested in understanding the extent to which the aging of hematopoietic stem and progenitor cells contributes to the pathophysiological conditions arising in the aged hematopoietic system, which include; declining immuno-competence, diminished stress response, anemia, and cancer. To address this we are evaluating hematopoietic stem and progenitor cells in the context of aging in order to determine the cellular and molecular mechanisms underlying the aging of the hematopoietic system. In particular we are exploring the contribution of epigenetic regulatory mechanisms to hematopoietic stem cell biology and aging. We are also studying the mechanisms through which stem cells maintain genomic integrity, and examining how age-dependent DNA damage accrual impacts stem cell functional capacity to contribute to hematopoietic pathophysiology.
Numerous studies have shown that it is possible to experimentally reprogram the cellular identity of one cell type to another. One approach to effect cellular reprogramming involves enforcing expression of defined transcriptional regulators important for specifying one cell type in a different cell type in order to convert its fate. This methodology is perhaps best exemplified by the generation of induced pluripotent stem (iPS) cells from a variety of differentiated cell types by the ectopic expression of a small number of defined factors. This approach is also proving to be a viable method to reprogram a variety of cell types to alternative fates. Our lab is pursuing several lines of investigation aimed at reprogramming the cellular identity of a number of cell types into clinically useful cell types through various approaches including the use of a powerful new technology developed in the lab.
1. Beerman, I, Bhattacharya, D, Zandi, S, Sigvardsson, M, Weissman, IL, Bryder, D, Rossi, DJ. Functionally distinct hematopoietic stem cells modulate hematopoietic lineage potential during aging by a mechanism of clonal expansion. PNAS, Mar 23;107(12):5465-70, 2010. PMC2851806
2. Bock, C, Beerman I, Rossi DJ, Meissner, A, DNA methylation dynamics during in vivo differentiation of blood and skin stem cells. Mol Cell, 2012 Aug 24;47(4):633-47. Epub 2012 Jul 26. PMC Journal in process.
3. Beerman I, Bock C, Garrison B, Smith Z, Gu H, Meissner A, and Rossi DJ. Proliferation-Dependent Alterations of the DNA Methylation Landscape Underlie Hematopoietic Stem Cell Aging. Cell Stem Cell. 2013 Feb 13. [Epub ahead of print]. PMC Journal in process.
4. Mandal PK, Rossi DJ. Reprogramming human fibroblasts to pluripotency using modified mRNA. Nat Protoc Feb 21;8(3):568-82, 2013. PMC Journal in process.
5. Warren, LA, Manos, P, Ahfeldt, T, Loh, YH, Li, H, Lau, F, Ebina, W, Mandal, PK, Smith, ZD, Meissner, A, Daley, GQ, Brack, AS, Collins, JJ, Cowan, CA, Schlaeger, TM, Rossi, DJ. Highly efficient reprogramming to pluripotency and directed differentiation of human cells with synthetic modified mRNA. Cell Stem Cell, Nov 5;7(5):618-30, 2010. Epub 2010 Sep 30. PMC Journal in process.
Last Update: 1/6/2014