Person:
Hoggatt, Jonathan

Profile Picture

Email Address

AA Acceptance Date

Birth Date

Research Projects

Organizational Units

Job Title

Last Name

Hoggatt

First Name

Jonathan

Name

Hoggatt, Jonathan
Author's Publications: search.filters.isAuthorOfPublication.9fcdca75-8feb-41e1-b65b-5728b78ed35f

Search Results

Now showing 1 - 4 of 4
  • Thumbnail Image
    Publication
    Differential Stem and Progenitor Cell Trafficking by Prostaglandin E2
    (2013) Hoggatt, Jonathan; Mohammad, Khalid S.; Singh, Pratibha; Hoggatt, Amber F.; Chitteti, Brahmananda Reddy; Speth, Jennifer M.; Hu, Peirong; Poteat, Bradley A.; Stilger, Kayla N.; Ferraro, Francesca; Silberstein, Lev; Wong, Frankie K.; Farag, Sherif S.; Czader, Magdalena; Milne, Ginger L.; Breyer, Richard M.; Serezani, Carlos H.; Scadden, David; Guise, Theresa; Srour, Edward F.; Pelus, Louis M.
    SUMMARY To maintain lifelong production of blood cells, hematopoietic stem cells (HSC) are tightly regulated by inherent programs and extrinsic regulatory signals received from their microenvironmental niche. Long-term repopulating HSC (LT-HSC) reside in several, perhaps overlapping, niches that produce regulatory molecules/signals necessary for homeostasis and increased output following stress/injury 1–5. Despite significant advances in specific cellular or molecular mechanisms governing HSC/niche interactions, little is understood about regulatory function within the intact mammalian hematopoietic niche. Recently, we and others described a positive regulatory role for Prostaglandin E2 (PGE2) on HSC function ex vivo 6,7. While exploring the role of endogenous PGE2 we unexpectedly observed hematopoietic egress after nonsteroidal anti-inflammatory drug (NSAID) treatment. Surprisingly, this was independent of the SDF-1/CXCR4 axis. Stem and progenitor cells were found to have differing mechanisms of egress, with HSC transit to the periphery dependent on niche attenuation and reduction in the retentive molecule osteopontin (OPN). Hematopoietic grafts mobilized with NSAIDs had superior repopulating ability and long-term engraftment. Treatment of non-human primates and healthy human volunteers confirmed NSAID-mediated egress in higher species. PGE2 receptor knockout mice demonstrated that progenitor expansion and stem/progenitor egress resulted from reduced EP4 receptor signaling. These results not only uncover unique regulatory roles for EP4 signaling in HSC retention in the niche but also define a rapidly translatable strategy to therapeutically enhance transplantation.
  • Thumbnail Image
    Publication
    Survivin Modulates Genes with Divergent Molecular Functions and Regulates Proliferation of Hematopoietic Stem Cells through Evi-1
    (2014) Fukuda, Seiji; Hoggatt, Jonathan; Singh, Pratibha; Abe, Mariko; Speth, Jennifer M.; Hu, Peirong; Conway, Edward M.; Nucifora, Giuseppina; Yamaguchi, Seiji; Pelus, Louis M.
    The inhibitor of apoptosis protein Survivin regulates hematopoiesis, although its mechanisms of regulation of hematopoietic stem cells (HSCs) remain largely unknown. While investigating conditional Survivin deletion in mice, we found that Survivin was highly expressed in phenotypically defined HSCs and Survivin deletion in mice resulted in significantly reduced total marrow HSC and progenitor cells (HPC). Transcriptional analysis of Survivin−/− HSCs revealed altered expression of multiple genes not previously linked to Survivin activity. In particular, Survivin deletion significantly reduced expression of the Evi-1 transcription factor indispensable for HSC function, and the downstream Evi-1 target genes Gata2, Pbx1 and Sall2. The loss of HSCs following Survivin deletion and impaired long-term HSC repopulating function could be partially rescued by ectopic Evi-1 expression in Survivin −/− HSCs. These data demonstrate that Survivin partially regulates HSC function by modulating the Evi-1transcription factor and its downstream targets and identify new genetic pathways in HSCs regulated by Survivin.
  • Thumbnail Image
    Publication
    Non-genotoxic conditioning for hematopoietic stem cell transplantation using a hematopoietic-cell-specific internalizing immunotoxin
    (Springer Nature, 2016) Palchaudhuri, Rahul; Saez, Borja; Hoggatt, Jonathan; Schajnovitz, Amir; Sykes, David; Tate, Tiffany A; Czechowicz, Agnieszka; Kfoury, Youmna; Ruchika, FNU; Rossi, Derrick; Verdine, Gregory; Mansour, Michael; Scadden, David
    Hematopoietic stem cell transplantation (HSCT) offers curative therapy for patients with hemoglobinopathies, congenital immunodeficiencies, and other conditions, possibly including AIDS. Autologous HSCT using genetically corrected cells would avoid the risk of graft-versus-host disease (GVHD), but the genotoxicity of conditioning remains a substantial barrier to the development of this approach. Here we report an internalizing immunotoxin targeting the hematopoietic-cell-restricted CD45 receptor that effectively conditions immunocompetent mice. A single dose of the immunotoxin, CD45–saporin (SAP), enabled efficient (>90%) engraftment of donor cells and full correction of a sickle-cell anemia model. In contrast to irradiation, CD45–SAP completely avoided neutropenia and anemia, spared bone marrow and thymic niches, enabling rapid recovery of T and B cells, preserved anti-fungal immunity, and had minimal overall toxicity. This non-genotoxic conditioning method may provide an attractive alternative to current conditioning regimens for HSCT in the treatment of non-malignant blood diseases.
  • Thumbnail Image
    Publication
    Role of lipegfilgrastim in the management of chemotherapy-induced neutropenia
    (Dove Medical Press, 2015) Hoggatt, Jonathan; Tate, Tiffany A; Pelus, Louis M
    Chemotherapy, irradiation, and other agents are widely used to target the process of cell division in neoplastic cells. However, while these therapies are effective against most cancers, the high proliferative rate of the cells of the hematopoietic system that produce billions of blood cells needed daily throughout life is extremely sensitive to these agents, resulting in loss of blood cell populations, which can be life threatening. Neutropenia is the most serious hematologic toxicity of chemotherapy, which can result in patient morbidity and mortality due to opportunistic infection and often is the limiting factor in dose escalation or duration of chemotherapeutic administration. Neutropenic patients often require hospitalization and incur substantial medical costs associated with anti-infective therapy. Treatment of iatrogenic and congenic neutropenia was changed in the early 1990s with the introduction of filgrastim (Neupogen®) and pegfilgrastim (Neulasta®). With the expiration of patent lives of both of these drugs, biosimilars have begun to emerge. In this review, we will summarize the chemical characteristics, pharmacokinetics, safety and efficacy of lipegfilgrastim (Lonquex®), the first long-acting biosimilar filgrastim to receive regulatory approval and enter the marketplace.