PCMM | Highlights

 July 13, 2016

Dr. Isabel Beerman awarded a NIH Career Development Grant (K01) from the National Institute of Aging

Dr. Beerman, an Instructor in Pediatrics in Dr. Derrick Rossi’s laboratory, has received a five-year career development award to establish the potential of aged blood cells to be reprogrammed to cells with hematopoietic stem cell function. 

Aging of the blood system is associated with many detrimental phenotypes having clinical significance including anemia, increased autoimmunity, and elevated rates of malignancy. Increasing evidence implicates age-associated alterations of the hematopoietic stem cell (HSC) compartment as a primary source of hematopoietic dysregulation. Under Dr. Rossi’s mentorship, Dr. Beerman has established functional, molecular, and epigenetic changes in the aged HSC compartment that underlie aging phenotypes, in a cell-autonomous manner. These findings suggest that restoring functional potential to the aged HSC compartment will mitigate many negative phenotypes associated with blood aging. 

By examining transcriptional as well as epigenetic landscapes of the reprogrammed, or partially reprogrammed blood cells, Dr. Beerman will establish the potential for functional restoration of an aged blood system through reprogramming. 

November 6, 2014

A promising strategy against HIV

Harvard researchers genetically ‘edit’ human blood stem cells

By: B. D. Colen, Harvard Staff Writer

Harvard Stem Cell Institute (HSCI) researchers at Massachusetts General(MGH) and Boston Children’s hospitals (BCH) for the first time have used a relatively new gene-editing technique to create what could prove to be an effective technique for blocking HIV from invading and destroying patients’ immune system

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August 14, 2014

1 in 20,000: Identifying hematopoietic stem cells in bone marrow

Roi Gazit, Pankaj Mandal and Derrick Rossi have engineered a hematopoietic stem cell specific reporter mouse that permits facile detection of rare blood forming stem cells based on single color fluorescence.

Hematopoietic stem cells (HSCs) are at the forefront of regenerative medicine by virtue of their potential to reestablish hematopoiesis through self-renewal and differentiation upon transplantation. Extensively studied for the past 50 years, HSCs biology has laid many paradigms of adult tissue-specific stem cells.  Given the paucity of HSCs in human and murine bone marrow, an array of immunophenotypic markers are used to identify and isolate them. Immunophenotypic identity of HSCs varies greatly during ontogeny, location, upon mobilization and under ex vivo culture. This limits our understanding of HSC regulation, self-renewal, ex vivo maintenance, expansion and differentiation.

Genetic labeling of cells using gene-specific reporter expression is a great genetic tool to identify, mark and track a specific cell-type in vivo. A team of scientists led by Dr. Derrick Rossi at PCMM, Boston Children’s Hospital set out to identify set of genes that are specifically expressed within HSC compartment. Using a large number of microarray data sets of every cell types of murine hematopoietic system, the Rossi lab found a set of 40 plus genes with HSC-restricted expression. From this set of genes, post-doctoral fellows Roi Gazit and Pankaj K. Mandal, the lead authors of the study, targeted one such HSC-specific gene, Fgd5, by knocking in a reporter cassette into the endogenous Fgd5 locus to generate knock-in reporter mouse strain with HSC-restricted expression. The findings published in the latest issue of The Journal of Experimental Medicine (Volume 211 (7) 1315-1331) demonstrate that reporter expression faithfully and near-exclusively marks HSCs in murine bone marrow with reporter expression correlating with the well established immunophenotypic markers used to identify and isolate HSCs.

Dr. Rossi points to the importance of Fgd5 HSC-specific reporter strains of mice for hematopoietic stem cell community, “This is the first HSC-specific genetic resource developed, and I believe it will become a very widely used genetic tool for studying HSC biology to provide insights into improving their therapeutic potential”. Rossi and colleague also developed Tamoxifen-inducible Cre recombinase (CreERT2) knock-in strain of mice at the Fgd5 locus to permit ablation of genes specifically within HSC-compartment. “This will be very helpful in studying the role of various genes in HSC biology and will allow lineage tracing during ontogeny and differentiation process” explains Pankaj K. Mandal, one of the lead authors of the study. Ultimately, Rossi and colleagues think that HSC-reporter strain they’ve developed will be useful in identifying the conditions for expansion of HSCs outside the body, which could have significant potential for HSC transplantation procedures. 


July 7, 2014

The costs of quiescence, for cars and blood cells

By Tom Ulrich

My first car was my grandfather’s 1980 Chevrolet Malibu. For about two years before my family gave it to me, it sat unused in Grandpa’s garage—just enough time for all of the belts and hoses to rot and the battery to trickle down to nothing. 

Why am I telling this story? Because it’s much like what happens to the DNA in our blood-forming stem cells as we age. 

Hematopoietic stem cells (HSCs) spend very little of their lives in an active, cycling state. Much of the time they’re quiescent or dormant, keeping their molecular and metabolic processes dialed down. These quiet periods allow the cells to conserve resources, but also give time an opportunity to wear away at their genes. 

“DNA damage doesn’t just arise from mistakes during replication,” explains Derrick Rossi, PhD, a stem cell biology researcher with Boston Children’s Hospital’s Program in Cellular and Molecular Medicine. “There are many ways for damage to occur during periods of inactivity, such as reactions with byproducts of our oxidative metabolism.” 

The canonical view has been that HSCs always keep one eye open for DNA damage and repair it, even when dormant. But in a study recently published in Cell Stem Cell, Rossi and his team found evidence to the contrary­­—which might tell us something about age-related blood cancers and blood disorders.

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April 29, 2014

Can blood cells be rebooted into blood stem cells?

By Tom Ulrich

Think, for a moment, of a cell as a computer, with its genome as its software, working to give cells particular functions. One set of genetic programs turns a cell into aheart cell, another set creates a neuron, still another a lymphocyte and so on. The job of controlling which programs get booted up, and when, falls in part to transcription factors—genes that act like molecular switches to turn other genes on and off. 

Derrick Rossi, PhD, spends a lot of his time thinking about transcription factors. A stem cell and blood development researcher in Boston Children’s Hospital’s Program in Cellular and Molecular Medicine, Rossi believes that transcription factors hold the power to achieve one of the most sought-after goals in regenerative medicine: producing, from other cell types, transplantable hematopoietic stem cells (HSCs).

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 April 24, 2014

Scientists turn back the clock on blood cells, reprogram them into blood stem cells

Induced hematopoietic stem cells, or iHSCs, bear characteristic features of natural HSCs, represent milestone in regenerative medicine

By Tom Ulrich

Researchers at Boston Children's Hospital have reprogrammed mature blood cells from mice into blood-forming hematopoietic stem cells (HSCs), using a cocktail of eight genetic switches called transcription factors. The reprogrammed cells, which the researchers have dubbed induced HSCs (iHSCs), have the functional hallmarks of HSCs, are able to self-renew themselves like HSCs, and can give rise to all of the cellular components of the blood like HSCs.

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