Biologic and medical implications of the bone marrow niche.

The stem cell niche represents a means by which tissue needs are transmitted to individual stem cells under homeostatic and stress conditions. The Scadden lab demonstrated that modifications of the niche pharmacologically can alter regenerative outcomes with transplantation. Further, the Scadden lab showed that primary genetic alterations in niche cells can result in hematopoietic dysplasia and neoplasia including frank leukemia. These findings indicate that the niche can be therapeutically targeted and that it can be central to the initiation of malignancy.

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Hematopoietic stem cells have clone-specific epigenetically scripted behaviors and limited plasticity.

Using fluorescent tagging of endogenous HSC, the Scadden lab showed that stem cells have clone-specific functional characteristics governed by epigenetic programming. These data rebut the notion that HSC are a highly plastic population of cells whose response is shaped by exogenous triggers. Rather, they are a heterogeneous collection of diversely functioning cells. Depending on how physiologic challenges alter specific clonal responses and clonal diversity will affect host resilience or vulnerability to stress.

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HSC localization cues can be defined and manipulated to alter hematopoietic outcomes.

Scadden lab demonstrated that downregulation of CXCR4 led to massive movement of HSC from the bone marrow to the blood. This was the first documentation of the ability to mobilize stem cells through pharmacologic modification of CXCR4. Since, the Scadden lab has defined other molecules important in the trafficking of HSC such as G-alpha-s, the calcium sensing receptor and heparan sulfates. Two of these three findings have resulted in clinical trials or drugs. Further, the Scadden lab showed that specific immunotoxins efficiently condition for HSC transplant with minimal toxicity, a technonlogy now being commercially advanced for non-malignant hematologic disease and gene therapy.

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Molecular regulators of HSC quiescence and unique metabolic dependencies of myeloid malignancies.

The Scadden lab assessed and demonstrated distinct molecular control of cell cycling in stem and progenitor cells [note: the standard assays of the time are now recognized as informative of progenitor, not stem cell function]. They thereby demonstrated that HSC quiescence is necessary for long-term stem cell preservation and that targeting specific CDKI could have differential effects on HSC function. Further, the Scadden lab demonstrated distinctive metabolic dependencies of stem and progenitor cells that their malignant counterparts are far more vulnerable to metabolic perturbations, offering potential therapeutic windows now being tested in clinical trials.

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HSCs are a sanctuary from HIV infection and stem cell transplant effectively treats AIDS related lymphomas.

To assess the impact of HIV on HSCs, Scadden developed a function-based stem cell isolation method for human stem cells and determined that they are resistant to HIV-1 infection despite co-receptor expression. Scadden then designed and oversaw the first U.S. multi-center autologous stem cell transplantation trial in AIDS patients and conducted gene therapy studies in AIDS patients.

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Non-Traditional Roles of Blood and Bone Marrow

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