Dissertation Year Fellowship
UCLA Graduate Division
Bio
Tiancheng Fang is currently a postdoctoral fellow at Harvard Stem Cell Institute/Massachusetts General Hospital, Boston MA, advised by David Scadden M.D. Before joining Scadden Lab she earned her Ph.D. in Molecular and Medical Pharmacology Department at University of California, Los Angeles, advised by John P. Chute M.D .
Tiancheng's research focuses on enhancing T cell lymphopoiesis and thymus regeneration. She also had research experience in hematopoietic stem cell regeneration, protein crystallography , cancer biology and immunology.
Recent Honors
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2019
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2018
American Society of Hematology Abstract Achievement Award
American Society of Hematology
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2016
Winner of 6th annual BSC Venture Team Competition
UCLA Business of Science Center
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2013
Award for Excellence in Scientific Research and Presentation
UCLA Cross-disciplinary Scholars in Science and Technology Program
Education
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Ph.D. 2020
Doctor of Philosophy in Molecular and Medical Pharmacology
University of California, Los Angeles
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B.S.2014
Bachelor of Science in Biological Science
Nankai University, Tianjin, China
Research Experience
Tiancheng Fang now works as a Postdoctoral Fellow at Harvard Stem Cell Institute/Massachusetts General Hospital, directed by David Scadden, M.D.
Current Work Status
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Present 10/2020
Harvard Stem Cell Institute/Massachusetts General Hospital
Mentor: David Scadden, M.D.
Discovering novel mechanisms of thymus regeneration.
Past Research Experience
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09/2020 03/2015
UCLA Broad Stem Cell Research Center
Mentor: John Chute, M.D
Determine mechanism of EGFR signaling-mediated hematopoietic stem cell regeneration.
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03/2015 01/2015
UCLA Molecular Biology Institute
Mentor: Steven Bensinger, V.M.D., Ph.D.
Assess transcription profile of type I interferon signaling in macrophage after perturbation of cholesterol synthesis.
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12/2014 09/2014
UCLA Ahmanson Translational Imaging Division
Mentor: David Nathanson, Ph.D.
Examine efficacy of combination therapy by targeting EGFR signaling and glucose metabolism in glioblastoma.
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06/2014 06/2012
Nankai University Department of Genetics and Cell Biology
Mentor: Junjie Hu, Ph.D.
Determine function of membrane protein LGG-1 and LGG-2 in autophagosome formation.
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08/2013 06/2013
UCLA Department of Bioengineering
Mentor: Dino Di Carlo, Ph.D.
Identify inhibitors of Streptococcus caused biofilm formation with microfluidics.
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05/2012 11/2010
State Key Laboratory of Medicinal Chemical Biology (Nankai Univeristy)
Mentor: Zihe Rao, Ph.D.
Determine 3D-structure of RNA-binding proteins in Mycobacterium tuberculosis by X ray crystallography.
Publications
A list of my recent publications. Due to copyright issues, downloads are not available to download here.
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Chronic Myelogenous Leukemia Stem Cells Require Cell-autonomous Pleiotrophin Signaling
Journal Papers The Journal of Clinical Investigation. 130, pp. 315–328, (2020). The American Society for Clinical Investigation.
Abstract
Tyrosine kinase inhibitors (TKIs) induce molecular remission in the majority of patients with chronic myelogenous leukemia (CML), but the persistence of CML stem cells hinders cure and necessitates indefinite TKI therapy. We report that CML stem cells upregulate the expression of pleiotrophin (PTN) and require cell-autonomous PTN signaling for CML pathogenesis in BCR/ABL+ mice. Constitutive PTN deletion substantially reduced the numbers of CML stem cells capable of initiating CML in vivo. Hematopoietic cell-specific deletion of PTN suppressed CML development in BCR/ABL+ mice, suggesting that cell-autonomous PTN signaling was necessary for CML disease evolution. Mechanistically, PTN promoted CML stem cell survival and TKI resistance via induction of Jun and the unfolded protein response. Human CML cells were also dependent on cell-autonomous PTN signaling, and anti-PTN antibody suppressed human CML colony formation and CML repopulation in vivo. Our results suggest that targeted inhibition of PTN has therapeutic potential to eradicate CML stem cells.
PTPσ Inhibitors Promote Hhematopoietic Stem Cell Regeneration
Journal Papers Nature Communications. 10, p. 3667, (2019). Nature Publishing Group UK.
Abstract
Receptor type protein tyrosine phosphatase-sigma (PTPσ) is primarily expressed by adult neurons and regulates neural regeneration. We recently discovered that PTPσ is also expressed by hematopoietic stem cells (HSCs). Here, we describe small molecule inhibitors of PTPσ that promote HSC regeneration in vivo. Systemic administration of the PTPσ inhibitor, DJ001, or its analog, to irradiated mice promotes HSC regeneration, accelerates hematologic recovery, and improves survival. Similarly, DJ001 administration accelerates hematologic recovery in mice treated with 5-fluorouracil chemotherapy. DJ001 displays high specificity for PTPσ and antagonizes PTPσ via unique non-competitive, allosteric binding. Mechanistically, DJ001 suppresses radiation-induced HSC apoptosis via activation of the RhoGTPase, RAC1, and induction of BCL-XL. Furthermore, treatment of irradiated human HSCs with DJ001 promotes the regeneration of human HSCs capable of multilineage in vivo repopulation. These studies demonstrate the therapeutic potential of selective, small-molecule PTPσ inhibitors for human hematopoietic regeneration.
Grb10 Is a Tumor Suppressor in Human Acute Myeloid Leukemia
Journal Papers Blood. 132, pp. 1344–1344, (2018). American Society of Hematology.
Abstract
Acute myeloid leukemia (AML) is a common and potentially fatal hematologic malignancy. Allogeneic stem cell transplantation is the only curative therapy for most subtypes of AML, but carries a significant risk of transplant-related mortality. The development of novel therapies to eradicate AML remains a substantial area of unmet medical need. Growth factor receptor bound protein 10 (Grb10) is a member of the family of imprinted genes. Our laboratory demonstrated that in normal hematopoietic system, deletion of the maternal allele of Grb10 significantly increased hematopoietic stem cell long-term repopulating capacity (Yan et al. Cell Rep 2016). Grb10 has been shown to bind the intracellular domain of various tyrosine kinase receptors, e.g. KIT, FLT3 and RET, as well as low-density lipoprotein receptor-related protein 6, a negative regulator of the Wnt/β-catenin pathway. Analyzing RNAseq data from the Leucegene Project, we found that Grb10 is expressed on the majority of patient AML samples regardless of leukemia mutation profile. Silencing of Grb10 expression via Grb10 shRNA increased the proliferation and colony forming capacity of human AML cell lines, Kasumi-1, THP-1 and OCI-AML3 in vitro (p<0.0001 and p<0.01). Conversely, overexpression of Grb10 suppressed human AML cell growth (p<0.05). In order to determine the role of Grb10 in regulating AML growth in vivo, we transduced bone marrow lineage negative cells from mice with Grb10 maternal allele deletion (Grb10 m/+) and wild type (Grb10 +/+) mice with HoxA9-Meis1-neo-MSCV (gift from G. Savageau) and transplanted the progeny into congenic mice. Primary and secondary mice transplanted with Grb10m/+ HoxA9-Meis1 leukemia cells displayed significantly decreased survival compared to mice transplanted with Grb10+/+ HoxA9-Meis1 cells (p<0.001 and p<0.05). Furthermore, leukemia cells with Grb10 maternal allele deletion displayed an increase cell cycle progression and increased leukemia colony forming capacity. RNAseq analysis of Grb10 m/+ leukemia cells from diseased mice revealed significant dysregulation of the canonical Wnt/β catenin signaling pathway compared to Grb10 +/+ mice. RT-qPCR analysis confirmed that Wnt/β-catenin target genes, including MYC, CCND1, and SOX2 were significantly up-regulated in Grb10 knockdown human AML cells lines. Taken together, these data suggest that Grb10 is a powerful tumor suppressor in human AML, and represents a novel mechanistic target for the development of new therapies for human AML.
Epidermal Growth Factor Rejuvenates Aging Hematopoietic Stem Cells
Journal Papers Blood. 132, pp. 1284–1284, (2018). American Society of Hematology.
Abstract
Aging hematopoietic stem cells display distinct abnormalities such as myeloid skewing, decreased repopulating capacity, and leukemia predisposition. Radiation exposure potentiates aging of the hematopoietic system, as evidenced by premature and persistent senescence of HSCs in mice exposed to moderate dose irradiation (Blood, 2014. 123(20): p. 3105-15). Our laboratory demonstrated that EGF promotes hematopoietic stem cell (HSC) regeneration after radiation injury (Nat Med, 2013. 19(3): p. 295-304). Based on these results, we hypothesized that EGF and EGFR signaling may have rejuvenating effects on aging HSCs. For comparisons of young and aged mice, we utilized 2-4 month old mice and >18-24 month old female C57BL/6 mice, respectively. We discovered that aged C57BL/6 mice have decreased levels of EGF in the peripheral blood compared to young mice (p= 0.02) and decreased expression of EGFR on bone marrow (BM) ckit+sca-1+lin- (KSL) stem/progenitor cells (p= 0.03). BM KSL cells from aged mice displayed increased DNA damage in culture with thrombopoietin, SCF and Flt-3 ligand (TSF) compared to young KSL cells (p< 0.0001). Aged BM KSL cells treated with 100 ng/ml EGF had decreased DNA damage compared to aged BM KSL cells treated with TSF only (p< 0.01) Treatment with EGF for 7 days increased the colony forming capacity of aged BM KSL cells (p< 0.01). Importantly, competitive repopulation assays revealed that 7 day in vitro treatment of aged BM KSL cells with EGF significantly increased primary donor cell engraftment (p< 0.01) at 16 weeks compared to aged BM KSL cells cultured with TSF alone. Based on these in vitro observations, we next tested whether systemic administration of a recombinant, pegylated EGF (pEGF), 20 mcg three times weekly for 4 weeks could alter the hematopoietic characteristics of aged C57BL/6 mice. pEGF treatment decreased BM myeloid skewing (p< 0.01) and increased CD3 T cell content (p< 0.01) in aged mice compared to saline-injected controls. Furthermore, competitive repopulation assays revealed that pEGF treatment of aged mice caused a significant increase in functional HSCs capable of competitive engraftment in recipient congenic mice. Total primary donor cell (p< 0.01), myeloid cell (p< 0.01), T cell (p< 0.01) and B cell (p= 0.01) engraftment were significantly increased in recipient mice transplanted with BM cells from aged, pEGF-treated donors compared to recipients of aged, saline-treated donors at 20 weeks. Additionally, secondary transplantation also resulted in increased donor engraftment (p< 0.01) and increased donor myeloid engraftment (p< 0.05) at 12 weeks. These results suggested that systemic administration of pEGF rejuvenates the repopulating ability of aged HSCs. We next sought to determine if deficiency in EGFR signaling could accelerate hematopoietic aging in mice. For this purpose, we utilized a doxycycline-inducible, hematopoietic cell specific EGFR dominant negative mutant model (SCL-tTA;EGFR-DN mice). Interestingly, adult (13 month old) SCL-tTA;EGFR-DN mice displayed increased myeloid skewing in the peripheral blood (p< 0.05) and BM cells from SCL-tTA;EGFR-DN mice generated significantly decreased colony forming cells, compared to age-matched, EGFR-expressing mice (p< 0.01). Mechanistically, BM KSL cells from 13 month old SCL-tTA;EGFR-DN mice demonstrated increased senescence (p< 0.01) and increased expression of p16 (p< 0.05) compared to young mice. In contrast, BM KSL cells from aged C57BL/6 mice that were treated with 100 ng/ml EGF (plus TSF) for 7 days displayed decreased senescence and decreased p16 expression compared to BM KSL cells from aged mice treated with TSF alone. Taken together, these studies suggest that EGF/EGFR signaling declines with age and that reactivation of EGFR signaling via EGF treatment can ameliorate clinically relevant features of hematopoietic aging, including HSC self-renewal capacity.
Inhibition of Semaphorin 3A Signaling Promotes Regeneration of Hematopoietic Stem Cells and Their Bone Marrow Vascular Niche
Journal Papers Blood. 132, pp. 1292–1292, (2018). American Society of Hematology.
Abstract
Radiation injury damages both the bone marrow hematopoietic stem cell and its supportive endothelial niche. In response to radiation stress, bone marrow endothelial cells (BM ECs) upregulate expression of a gene, Sema3A, which encodes for the secreted protein, Semaphorin 3A (SEMA3A), and its receptor, Neuropilin 1 (Nrp1). Commensurate with this, we observed a substantial increase in SEMA3A protein levels in the BM of mice and in NRP1 expression on VE-cadherin+ BM ECs following 500 cGy total body irradiation (TBI) (p<0.001, p<0.0001). We also found that treatment of irradiated primary murine BM ECs with SEMA3A significantly increased BM EC apoptosis (p<0.01). Based on these results, we hypothesized that SEMA3A may be a negative regulator of BM vascular recovery following injury and that inhibition of SEMA3A/NRP1 signaling might accelerate BM vascular niche recovery following irradiation. In keeping with this hypothesis, we found that a single systemic administration of 2 µg SEMA3A (IV) to C57BL/6 mice following 500 cGy TBI significantly increased BM EC apoptosis in vivo at 24 hours and also markedly decreased BM vascular integrity at 24 hours as measured by Evans Blue Dye extravasation in the BM (p<0.01, p<0.01). Interestingly, SEMA3A administration (IV, every other day) also significantly suppressed BM hematopoietic regeneration with decreased BM cell counts and BM ckit+sca-1+lin- (KSL) progenitor cell recovery at day +10 compared to irradiated, control mice (p=0.04, p=0.001). In contrast, systemic administration of anti-NRP1 antibody (10 µg, IV every other day), which blocks SEMA3A binding to NRP1 on BM ECs, accelerated regeneration of the sinusoidal BM vasculature at day +10 following 500 cGy TBI compared to irradiated controls. Concordant with these findings, anti-NRP1 treatment increased the recovery of peripheral blood WBCs, neutrophils, and BM KSL cells, compared to irradiated controls (p=0.002, p=0.04, p=0.04). Competitive repopulation assays confirmed that anti-NRP1 treatment increased the recovery of long-term HSCs capable of 20-week multilineage repopulation in congenic mice (p=0.03 for % donor CD45.1+ cell engraftment at 20 weeks). Importantly, anti-NRP1 treatment also markedly improved 60-day survival of irradiated mice from 17% (2/12 controls) to 83% (10/12 anti-NRP1) following 800 cGy TBI. In order to confirm the role of SEMA3A/NRP1 signaling in BM ECs in regulating the BM vascular and hematopoietic response to injury, we generated mice with tamoxifen-inducible, EC - specific deletion of Nrp1 (VE-Cad-Cre-ERT2;Nrp1 fl/fl mice). Adult VE-Cad-Cre-ERT2;Nrp1 fl/fl mice were viable and had no baseline hematologic phenotype. However, following 500 cGy TBI, VE-Cad-Cre-ERT2;Nrp1 fl/fl mice displayed accelerated BM vascular regeneration at day +10 compared to irradiated control mice. Furthermore, VE-Cad-Cre-ERT2;Nrp1 fl/fl mice demonstrated significantly increased peripheral blood WBCs, neutrophils, and BM KSL cells at day +10 following radiation injury (p<0.001, p=0.002, p=0.002). These data suggest that the SEMA3A-NRP1 pathway is an autocrine signaling mechanism that negatively regulates BM vascular niche recovery following myelosuppressive irradiation. Targeted inhibition of SEMA3A-NRP1 signaling in BM ECs has therapeutic potential to accelerate both BM vascular niche regeneration and hematopoietic reconstitution following myelosuppression.
Distinct Bone Marrow Sources of Pleiotrophin Control Hematopoietic Stem Cell Maintenance and Regeneration
Journal Papers Cell stem cell. 23, pp. 370–381, (2018). Elsevier.
Abstract
Bone marrow (BM) perivascular stromal cells and vascular endothelial cells (ECs) are essential for hematopoietic stem cell (HSC) maintenance, but the roles of distinct niche compartments during HSC regeneration are less understood. Here we show that Leptin receptor-expressing (LepR+) BM stromal cells and ECs dichotomously regulate HSC maintenance and regeneration via secretion of pleiotrophin (PTN). BM stromal cells are the key source of PTN during steady-state hematopoiesis because its deletion from stromal cells, but not hematopoietic cells, osteoblasts, or ECs, depletes the HSC pool. Following myelosuppressive irradiation, PTN expression is increased in bone marrow endothelial cells (BMECs), and PTN+ ECs are more frequent in the niche. Moreover, deleting Ptn from ECs impairs HSC regeneration whereas Ptn deletion from BM stromal cells does not. These findings reveal dichotomous and complementary regulation of HSC maintenance and regeneration by BM stromal cells and ECs.
Deletion of the Imprinted Gene Grb10 Promotes Hematopoietic Stem Cell Self-renewal and Regeneration
Journal Papers Cell reports. 17, pp. 1584–1594, (2016). Elsevier.
Abstract
Imprinted genes are differentially expressed by adult stem cells, but their functions in regulating adult stem cell fate are incompletely understood. Here we show that growth factor receptor-bound protein 10 (Grb10), an imprinted gene, regulates hematopoietic stem cell (HSC) self-renewal and regeneration. Deletion of the maternal allele of Grb10 in mice (Grb10m/+ mice) substantially increased HSC long-term repopulating capacity, as compared to that of Grb10+/+ mice. After total body irradiation (TBI), Grb10m/+ mice demonstrated accelerated HSC regeneration and hematopoietic reconstitution, as compared to Grb10+/+ mice. Grb10-deficient HSCs displayed increased proliferation after competitive transplantation or TBI, commensurate with upregulation of CDK4 and Cyclin E. Furthermore, the enhanced HSC regeneration observed in Grb10-deficient mice was dependent on activation of the Akt/mTORC1 pathway. This study reveals a function for the imprinted gene Grb10 in regulating HSC self-renewal and regeneration and suggests that the inhibition of Grb10 can promote hematopoietic regeneration in vivo.
Structural Basis of the Differential Function of the Two C. elegans Atg8 Homologs, LGG-1 and LGG-2, in Autophagy
Journal Papers Molecular cell. 60, pp. 914–929, (2015). Elsevier.
Abstract
Multicellular organisms have multiple homologs of the yeast ATG8 gene, but the differential roles of these homologs in autophagy during development remain largely unknown. Here we investigated structure/function relationships in the two C. elegans Atg8 homologs, LGG-1 and LGG-2. lgg-1 is essential for degradation of protein aggregates, while lgg-2 has cargo-specific and developmental-stage-specific roles in aggregate degradation. Crystallography revealed that the N-terminal tails of LGG-1 and LGG-2 adopt the closed and open form, respectively. LGG-1 and LGG-2 interact differentially with autophagy substrates and Atg proteins, many of which carry a LIR motif. LGG-1 and LGG-2 have structurally distinct substrate binding pockets that prefer different residues in the interacting LIR motif, thus influencing binding specificity. Lipidated LGG-1 and LGG-2 possess distinct membrane tethering and fusion activities, which may result from the N-terminal differences. Our study reveals the differential function of two ATG8 homologs in autophagy during C. elegans development.
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