Rossi Laboratory

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. However, 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 the stem cell compartment contributes to the pathophysiological conditions arising in the aged hematopoietic system. To address this we are evaluating HSCs in the context of aging in order to elucidate the mechanistic basis for HSC decline. In particular we are exploring the contribution of epigenetic dysregulation to HSC 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. 

Contact

Research

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, including HSCs, by using various approaches including the use of powerful technologies developed in the lab. 

Generating patient-specific HSCs

Hematopoietic stem cells (HSCs) are arguably the best-characterized and most experimentally tractable tissue-specific stem cells. HSCs reside at the top of hematopoietic hierarchy and give rise to a large repertoire of highly specialized effector cells by differentiating through a succession of increasingly committed downstream progenitor cells. HSCs are the only cells in the hematopoietic system that possess the ability to both differentiate to all blood lineages and to self-renew for life. 

Read more

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. Allogeneic and autologous HSC transplantation are routinely used in the treatment of patients with a variety of life-threatening disorders.

Despite wide clinical use, HSC transplantation remains a high-risk procedure, with the number of stem cells available for transplantation being the strongest predictor of transplantation success. Moreover, despite increased efforts to find histocompatible donors for HSC recipients, graft-versus-host disease (GVHD) remains a significant cause of morbidity and mortality. Thus an ability to expand or generate patient-specific HSCs de novo from alternative cell sources would be transformative for a number of clinical settings. The Rossi lab is intensely focused on this challenge and towards this is developing strategies to generate patient-specific HSCs from induced pluripotent stem (iPS) cells, or to direct the fate of other cell types towards a definitive HSC fate. To do this we have generated a number of molecular resources, and developed a powerful modified-mRNA based technology that we have demonstrated can efficiently instruct cell fate in a number of settings.

Hematopoietic stem cell aging

While certainly one of the most recognizable aspects of human biology, aging remains one of the least understood. This is largely attributable to the fact that aging is both gradual, and inherently complex, with almost all aspects of our physiology and phenotype undergoing slow but steady modification with advancing age. Decades of study using diverse systems, model organisms and methodologies have built a consensus as to what the central physiology characteristics of aging systems are.

Indeed, these studies have suggested that regardless of the system being studied, aging is most often characterized as a failure to maintain tissue homeostasis, or to return to a homeostatic steady-state condition after exposure to stress or injury. The fact that both homeostasis and regeneration after injury in adult tissues is the purview of tissue-specific stem cells, has therefore implicated age-dependent stem cell decline in the aging process. Indeed work from our group and others has borne this out, and stem cell aging is now considered to be central to the aging of tissues and organisms. Our lab is currently elucidating both the genetic and epigenetic mechanisms underlying HSC age-associated decline.

Teaching

SCRB 130

Biomedical Entrepreneuring: Turning Ideas into Medicine

Medicines and other therapeutics have revolutionized the treatment of many diseases. Few of us pause to consider how these products are developed from an initial discovery in the lab to the treatment of patients. This course will consider this journey by incorporating scientific, biotechnology, intellectual property, venture capitol, and business perspectives. In addition to lectures, students will work on group projects to chart a strategy toward bringing a novel biomedical idea to the clinic.