- Pediatric Critical Care Medicine
Clinical Scholar, Pediatrics - Critical Care
Board Certification, American Board of Pediatrics, Pediatric Critical Care Medicine (2020)
Fellowship: Stanford University Pediatric Critical Care Fellowship (2020) CA
Board Certification: American Board of Pediatrics, Pediatrics (2017)
Residency: Cincinnati Children's Hospital Medical Center Pediatric Residency (2017) OH
Medical Education: Washington University School Of Medicine Registrar (2014) MO
Doctor of Philosophy, Washington University (2014)
Doctor of Medicine, Washington University (2014)
Bachelor of Arts, Johns Hopkins University (2001)
KRasG12D expression in the bone marrow vascular niche affects hematopoiesis with inflammatory signals.
The bone marrow (BM) niche is an important milieu where hematopoietic stem and progenitor cells (HSPCs) are maintained. Previous studies have shown that genetic mutations in various components of the niche can affect hematopoiesis and promote hematologic abnormalities, but the impact of abnormal BM endothelial cells (BMECs), a crucial niche component, on hematopoiesis remains incompletely understood. To dissect how genetic alterations in BMECs could affect hematopoiesis, we have employed a novel inducible Tie2-CreERT2 mouse model, with a tdTomato fluorescent reporter, to introduce an oncogenic KRasG12D mutation specifically in the adult endothelial cells. Tie2-CreERT2;KRasG12D mice had significantly more leukocytes and myeloid cells in the blood with mostly normal BM HSPC populations and developed splenomegaly. Genotyping PCR found KRasG12D activation in BMECs but not hematopoietic cells, confirming that the phenotype is due to the aberrant BMECs. Competitive transplant assays revealed that BM cells from the KRasG12D mice contained significantly lower functional hematopoietic stem cells (HSCs) and immunofluorescence imaging showed that HSCs in the mutant mice were localized farther away from BM vasculature and closer to the endosteal area. RNA-seq analyses found an inflammatory gene network, especially TNFα, as a possible contributor. Together, our results implicate an abnormal endothelial niche in compromising normal hematopoiesis.
View details for DOI 10.1016/j.exphem.2019.10.003
View details for PubMedID 31669153
Bone marrow dendritic cells regulate hematopoietic stem/progenitor cell trafficking.
The Journal of clinical investigation
2019; 129 (7): 2920–31
A resident population of dendritic cells (DCs) has been identified in murine bone marrow, but its contribution to the regulation of hematopoiesis and establishment of the stem cell niche is largely unknown. Here, we show that murine bone marrow DCs are perivascular and have a type 2 conventional DC (cDC2) immunophenotype. RNA expression analysis of sorted bone marrow DCs shows that expression of many chemokines and chemokine receptors is distinct from that observed in splenic cDC2s, suggesting that bone marrow DCs may represent a unique DC population. A similar population of DCs is present in human bone marrow. Ablation of conventional DCs (cDCs) results in hematopoietic stem/progenitor cell (HSPC) mobilization that is greater than that seen with ablation of bone marrow macrophages, and cDC ablation also synergizes with G-CSF to mobilize HSPCs. Ablation of cDCs is associated with an expansion of bone marrow endothelial cells and increased vascular permeability. CXCR2 expression in sinusoidal endothelial cells and the expression of two CXCR2 ligands, CXCL1 and CXCL2, in the bone marrow are markedly increased following cDC ablation. Treatment of endothelial cells in vitro with CXCL1 induces increased vascular permeability and HSPC transmigration. Finally, we show that HSPC mobilization after cDC ablation is attenuated in mice lacking CXCR2 expression. Collectively, these data suggest that bone marrow DCs play an important role in regulating HSPC trafficking, in part, through regulation of sinusoidal CXCR2 signaling and vascular permeability.
View details for DOI 10.1172/JCI124829
View details for PubMedID 31039135
View details for PubMedCentralID PMC6597218
Osteoclasts are dispensable for hematopoietic progenitor mobilization by granulocyte colony-stimulating factor in mice.
2015; 43 (2): 110–14.e1–2
The contribution of osteoclasts to hematopoietic stem/progenitor cell (HSPC) retention in the bone marrow is controversial. Studies of HSPC trafficking in osteoclast-deficient mice are limited by osteopetrosis. Here, we employed two non-osteopetrotic mouse models to assess the contribution of osteoclasts to basal and granulocyte colony-stimulating factor (G-CSF)-induced HSPC mobilization. We generated Rank(-/-) fetal liver chimeras using Csf3r(-/-) recipients to produce mice lacking G-CSF receptor expression in osteoclasts. Basal and G-CSF-induced HSPC mobilization was normal in these chimeras. We next acutely depleted osteoclasts in wild-type mice using the RANK ligand inhibitor osteoprotegerin. Marked suppression of osteoclasts was observed after a single injection of osteoprotegerin-Fc. Basal and G-CSF-induced HSPC mobilization in osteoprotegerin-Fc-treated mice was comparable to that in control mice. Together, these data indicate that osteoclasts are not required for the efficient retention of HSPCs in the bone marrow and are dispensable for HSPC mobilization by G-CSF.
View details for DOI 10.1016/j.exphem.2014.10.012
View details for PubMedID 25461255
View details for PubMedCentralID PMC4323843
Expression of the G-CSF receptor in monocytic cells is sufficient to mediate hematopoietic progenitor mobilization by G-CSF in mice.
The Journal of experimental medicine
2011; 208 (2): 251–60
Granulocyte colony-stimulating factor (G-CSF), the prototypical mobilizing cytokine, induces hematopoietic stem and progenitor cell (HSPC) mobilization from the bone marrow in a cell-nonautonomous fashion. This process is mediated, in part, through suppression of osteoblasts and disruption of CXCR4/CXCL12 signaling. The cellular targets of G-CSF that initiate the mobilization cascade have not been identified. We use mixed G-CSF receptor (G-CSFR)-deficient bone marrow chimeras to show that G-CSF-induced mobilization of HSPCs correlates poorly with the number of wild-type neutrophils. We generated transgenic mice in which expression of the G-CSFR is restricted to cells of the monocytic lineage. G-CSF-induced HSPC mobilization, osteoblast suppression, and inhibition of CXCL12 expression in the bone marrow of these transgenic mice are intact, demonstrating that G-CSFR signals in monocytic cells are sufficient to induce HSPC mobilization. Moreover, G-CSF treatment of wild-type mice is associated with marked loss of monocytic cells in the bone marrow. Finally, we show that bone marrow macrophages produce factors that support the growth and/or survival of osteoblasts in vitro. Together, these data suggest a model in which G-CSFR signals in bone marrow monocytic cells inhibit the production of trophic factors required for osteoblast lineage cell maintenance, ultimately leading to HSPC mobilization.
View details for DOI 10.1084/jem.20101700
View details for PubMedID 21282380
View details for PubMedCentralID PMC3039862
Carbon monoxide mediates vasoactive intestinal polypeptide-associated nonadrenergic/noncholinergic neurotransmission.
Proceedings of the National Academy of Sciences of the United States of America
2004; 101 (8): 2631–35
Carbon monoxide (CO) synthesized by heme oxygenase 2 (HO2) and nitric oxide (NO) produced by neuronal NO synthase (nNOS) mediate nonadrenergic/noncholinergic (NANC) intestinal relaxation. In many areas of the gastrointestinal tract, NO and CO function as coneurotransmitters. In the internal anal sphincter (IAS), NANC relaxation is mediated primarily by CO. Vasoactive intestinal polypeptide (VIP) has also been shown to participate in NANC relaxation throughout the intestine, including the IAS. By using a combination of pharmacology and genetic knockout of the biosynthetic enzymes for CO and NO, we show that the physiologic effects of exogenous and endogenous VIP in the IAS are mediated by HO2-synthesized CO.
View details for DOI 10.1073/pnas.0308695100
View details for PubMedID 14983060
View details for PubMedCentralID PMC357001
Biliverdin reductase: a major physiologic cytoprotectant.
Proceedings of the National Academy of Sciences of the United States of America
2002; 99 (25): 16093–98
Bilirubin, an abundant pigment that causes jaundice, has long lacked any clear physiologic role. It arises from enzymatic reduction by biliverdin reductase of biliverdin, a product of heme oxygenase activity. Bilirubin is a potent antioxidant that we show can protect cells from a 10,000-fold excess of H2O2. We report that bilirubin is a major physiologic antioxidant cytoprotectant. Thus, cellular depletion of bilirubin by RNA interference markedly augments tissue levels of reactive oxygen species and causes apoptotic cell death. Depletion of glutathione, generally regarded as a physiologic antioxidant cytoprotectant, elicits lesser increases in reactive oxygen species and cell death. The potent physiologic antioxidant actions of bilirubin reflect an amplification cycle whereby bilirubin, acting as an antioxidant, is itself oxidized to biliverdin and then recycled by biliverdin reductase back to bilirubin. This redox cycle may constitute the principal physiologic function of bilirubin.
View details for DOI 10.1073/pnas.252626999
View details for PubMedID 12456881
View details for PubMedCentralID PMC138570