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Research at Mass General
Read the Hoggatt Lab 2017-2018 Annual Report
Jonathan G. Hoggatt, PhDSenior Investigator/Head, Hoggatt Lab, CTS
Assistant Professor of MedicineMassachusetts General Hospital,
Center for Transplantation SciencesHarvard Medical School
The Hoggatt Laboratory is broadly interested in the stem cell niche regulatory mechanisms that govern tissue regeneration, particularly regulation by macrophages, and that have a specific interest in translational science for bone marrow transplantation and other treatments. We have identified a unique “highly engraftable” hematopoietic stem cell that we are currently investigating which has applications for further probing of stem cell niche biology, and clinical applications in transplantation, gene therapy, and other fields. We have also developed unique genetic mouse models allowing us to dynamically explore macrophage heterogeneity in a variety of disease settings.
To learn more about the Hoggatt Laboratory, visit their website at hoggattlab.com.
Jonathan G. Hoggatt, PhDPrincipal Investigator
Macrophage Regulation of Tissue Regeneration
Macrophages are ancient cells of the innate and adaptive immune system. My old microbiology textbook defines macrophages as “scavengers and sentries – routinely phagocytizing dead cells and debris, but always on the lookout, ready to destroy invaders, and able to call in reinforcements when needed.” Our laboratory believes they are so much more.
Tissue resident macrophage populations exist in virtually every tissue, whether they are Kupffer cells in the liver, alveolar macrophages in the lung, microglia in the brain or Langerhans cells in the skin. Some of these macrophages have been recently reported to specify hepatic progenitor cell fate, regulate epithelial progenitor niches in the colon and drive oligodendrocyte differentiation during remyelination in the central nervous system. After depletion of macrophages, an adult salamander is unable to regenerate an amputated limb. However, when macrophage levels were allowed to replenish, full limb regeneration capacity of failed stumps was restored upon re-amputation. Macrophages, therefore, may be a common cellular regulator across a diverse repertoire of stem cell niches. The problem that exists today is that macrophages are extraordinarily diverse and plastic, necessitating the need to identify specific subsets responsible for stem cell and tissue regeneration, in both homeostatic and disease scenarios.
We have created a unique mouse model that allows tracking of macrophages with deferring embryonic origins with specific, genetic-fluorescent markers, aiding in de-convoluting this heterogeneous cell population. Our laboratory is exploring several clinically relevant applications for stem cell transplantation, and will broadly use these macrophage tools and knowledge to delineate macrophage regenerative signals in multiple tissue stem cell niches, organ transplantation, and disease.
Hematopoietic Stem Cell Biology
Hematopoietic stem cell (HSC) transplantation is used to treat a number of malignant and non-malignant diseases. Over the last decade, there has been increasing evidence that the HSC pool is heterogeneous in function; with identification of HSCs with differing lineage outputs, kinetics of repopulation, length of life-span, and perhaps differences amongst HSCs contributing to homeostatic blood production from those that are the engraftable units in transplantation. Delineating the mechanisms of these functional differences has the potential to increase the efficacy of stem cell transplantation.
Currently, there are no great methods for prospectively isolating differing HSC populations to study heterogeneity; much of the data that has been acquired is based on clonal tracking, single cell transplantation, etc. We have developed a rapid mobilization regimen as a new method to acquire HSCs. After fifteen minutes, a single subcutaneous injection in mice leads to mobilization that is greater than 5 days of granulocyte-colony stimulating factor (G-CSF) treatment; the current gold standard for hematopoietic mobilization. Surprisingly, when equivalent numbers of highly-purified HSCs from the blood of mice treated with the rapid regimen versus G-CSF were subsequently competitively transplanted into lethally irradiated recipients, the HSCs mobilized by the rapid regimen substantially outperformed those mobilized by G-CSF. The rapid regimen mobilizes a “highly engraftable” hematopoietic stem cell (heHSC) compared to those mobilized by G-CSF.
Much like panning for gold, we have used the differential mobilization properties of our regimen and G-CSF as a “biologic sieve” to isolate the heterogeneous HSC populations from the blood. Our laboratory will continue to leverage this approach to analyze the transcriptomic and epigenetic differences between the two populations of HSCs to determine the specific gene(s) that account for the heHSC phenotype and to further explore the biologic potential of this new population of stem cells. These efforts have the potential to substantially increase our knowledge of heterogeneity and increase efficacy of HSC based clinical therapies.
Shown are sinusoidal vessels (green) within the calvaria bone of mice during live, in vivo imaging of the hematopoietic stem cell niche.
Hoggatt J. Gene Therapy for ‘Bubble Boy’ Disease. Cell, 2016; Jul 14;166(2):263.
Palchaudhuri R, Saez B, Hoggatt J, Schajnovitz A, Sykes DB, Tate TA, Czechowicz A, Kfoury Y, Ruchika F, Rossi DJ, Verdine GL, Mansour MK, Scadden DT. Non-genotoxic conditioning for hematopoietic stem cell transplantation using a hematopoietic-cell-specific internalizing immunotoxin. Nature Biotechnology, 2016; Jul;34(7):738-45
Hoggatt J, Kfoury Y and Scadden DT. Hematopoietic Stem Cell Niche in Health and Diseases. Annual Review of Pathology, 2016;11:555-581.
Hoggatt J†*, Hoggatt AF†*, Tate TA, Fortman J, Pelus LM*. Bleeding the Laboratory Mouse: Not All Methods are Equal. Experimental Hematology, 2016: Feb;44(2):132-137.
Hoggatt J, Tate TA and Pelus LM. “Role of Lipegfilgrastim in the Management of Chemotherapy Induced Neutropenia. International Journal of Nanomedicine, 2015;10:2647-52.
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