Hematopoetic Stem Cell Niche

HSC respond to regenerative demand in vivo but expanding them ex vivo has frustrated investigators for decades. We sought to understand how HSC are governed in the bone marrow and used engineered mice to demonstrate the role for specific bone mesenchymal cells to alter hematopoietic stem cells. These data were the first demonstration of a specific heterologous cell regulating stem cells in mammals thereby validating the niche hypothesis in mammals as proposed by Raymond Schofield in 1978 [note: a co-published paper from Linheng Li’s lab also showed microenvironmental control of HSC in vivo though without cell specificity]. We have subsequently defined molecular regulators at the interface of stem cells and their niche and with Dr. Charles Lin, pioneered methods to reveal the microanatomy of the periendosteal and perivascular HSPC niches in live animals. Most recently, we developed a novel proximity-based differential single cell analysis of the niche to define new stem/progenitor cell regulators. These include a secreted RNAase that modifies tRNAs and protein production as a means of affecting stem/progenitor quiescence.

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We have used mouse models of acute myeloid leukemia to define distinct roles for FOXO proteins and markedly different metabolic dependencies of malignant cells and their normal cell counterparts. In recent work collaborating with Stuart Schreiber’s lab at the Broad Institute, we identified that inhibiting the mitochondrial enzyme, DHODH, can overcome the differentiation blockade in mouse and human AML cells and dramatically improve survival and tolerance of treatment over standard chemotherapy in animal models. These studies are translating to clinical testing.

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Hematopoetic Niche In Malignancy

The stem cell niche represents a means by which tissue needs are transmitted to stem cells under homeostatic and stress conditions. We demonstrated that modifications of the niche pharmacologically can alter regenerative outcomes under the stress of transplantation. Further, we showed that primary genetic alterations in niche cells can result in hematopoietic dysplastic and neoplastic disease 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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HSC Quiescence

Since HSC are notably distinct from more mature progenitor cells in terms of response to cytokines and cell cycling. We 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]. We thereby demonstrated that HSPC quiescence is necessary for long-term stem cell preservation and that targeting specific CDKI could have differential effects on HSPC function. Further, we demonstrated distinctive metabolic dependencies of stem and progenitor cells and that their malignant counterparts are far more vulnerable to metabolic perturbations, offering potential therapeutic windows now being tested in pre-clinical models.

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Trafficking Of HSCs

Human HSC are resistant to HIV infection despite the presence of cognate co-receptors for the virus. We therefore tested the role of specific chemokine receptors on HSC function in vivo in mice and demonstrated that downregulation of CXCR4 led to massive movement of HSC from the bone marrow to the blood. This was the first demonstration of the ability to mobilize stem cells through pharmacologic modification of CXCR4. We have since shown other molecules important in the trafficking of HSC such as Galphas, the calcium sensing receptor and heparan sulfates. Two of these three findings have resulted in clinical trials or drugs.

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HSC Resistance To HIV Infection

Working with HIV required the use of poorly characterized human hematopoietic stem cells and the lab developed a function-based stem cell isolation method that enabled single cell characterization of gene expression and defined the human HSC as being resistant to HIV-1 infection. We then oversaw the first U.S. multi-center autologous stem cell transplantation trial in AIDS patients.

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