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Article ; Online: Notch activation during early mesoderm induction modulates emergence of the T/NK cell lineage from human iPSCs.

Heinze, Dar / Park, Seonmi / McCracken, Andrew / Haratianfar, Mona / Lindstrom, Jonathan / Villacorta-Martin, Carlos / Mithal, Aditya / Wang, Feiya / Yang, Meng Wei / Murphy, George / Mostoslavsky, Gustavo

Stem cell reports

2022 Volume 17, Issue 12, Page(s) 2610–2628

Abstract: A robust method of producing mature T cells from iPSCs is needed to realize their therapeutic potential. NOTCH1 is known to be required for the production of hematopoietic progenitor cells with T cell potential in vivo. Here we identify a critical window ...

Abstract	A robust method of producing mature T cells from iPSCs is needed to realize their therapeutic potential. NOTCH1 is known to be required for the production of hematopoietic progenitor cells with T cell potential in vivo. Here we identify a critical window during mesodermal differentiation when Notch activation robustly improves access to definitive hematopoietic progenitors with T/NK cell lineage potential. Low-density progenitors on either OP9-hDLL4 feeder cells or hDLL4-coated plates favored T cell maturation into TCRab
MeSH term(s)	Humans ; Cell Lineage ; Mesoderm ; Induced Pluripotent Stem Cells ; T-Lymphocytes ; Cell Differentiation ; Receptors, Notch
Chemical Substances	Receptors, Notch
Language	English
Publishing date	2022-11-03
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2720528-9
ISSN	2213-6711 ; 2213-6711
ISSN (online)	2213-6711
ISSN	2213-6711
DOI	10.1016/j.stemcr.2022.10.007
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Generation of mesenchyme free intestinal organoids from human induced pluripotent stem cells.

Mithal, Aditya / Capilla, Amalia / Heinze, Dar / Berical, Andrew / Villacorta-Martin, Carlos / Vedaie, Marall / Jacob, Anjali / Abo, Kristine / Szymaniak, Aleksander / Peasley, Megan / Stuffer, Alexander / Mahoney, John / Kotton, Darrell N / Hawkins, Finn / Mostoslavsky, Gustavo

Nature communications

2020 Volume 11, Issue 1, Page(s) 215

Abstract: Efficient generation of human induced pluripotent stem cell (hiPSC)-derived human intestinal organoids (HIOs) would facilitate the development of in vitro models for a variety of diseases that affect the gastrointestinal tract, such as inflammatory bowel ...

Abstract	Efficient generation of human induced pluripotent stem cell (hiPSC)-derived human intestinal organoids (HIOs) would facilitate the development of in vitro models for a variety of diseases that affect the gastrointestinal tract, such as inflammatory bowel disease or Cystic Fibrosis. Here, we report a directed differentiation protocol for the generation of mesenchyme-free HIOs that can be primed towards more colonic or proximal intestinal lineages in serum-free defined conditions. Using a CDX2
MeSH term(s)	CDX2 Transcription Factor/metabolism ; Cell Differentiation ; Cystic Fibrosis ; Epithelial Cells ; Gene Knock-In Techniques ; Genetic Vectors ; Humans ; Induced Pluripotent Stem Cells/metabolism ; Intestine, Small ; Intestines/physiology ; Mesoderm/metabolism ; Organoids/cytology ; Organoids/metabolism ; Thyroid Nuclear Factor 1/genetics
Chemical Substances	CDX2 Transcription Factor ; CDX2 protein, human ; NKX2-1 protein, human ; Thyroid Nuclear Factor 1
Language	English
Publishing date	2020-01-10
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-019-13916-6
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Article ; Online: Transcriptional Immunoprofiling at the Tick-Virus-Host Interface during Early Stages of Tick-Borne Encephalitis Virus Transmission.

Thangamani, Saravanan / Hermance, Meghan E / Santos, Rodrigo I / Slovak, Mirko / Heinze, Dar / Widen, Steven G / Kazimirova, Maria

Frontiers in cellular and infection microbiology

2017 Volume 7, Page(s) 494

Abstract: Emerging and re-emerging diseases transmitted by blood feeding arthropods are significant global public health problems. Ticks transmit the greatest variety of pathogenic microorganisms of any blood feeding arthropod. Infectious agents transmitted by ... ...

Abstract	Emerging and re-emerging diseases transmitted by blood feeding arthropods are significant global public health problems. Ticks transmit the greatest variety of pathogenic microorganisms of any blood feeding arthropod. Infectious agents transmitted by ticks are delivered to the vertebrate host together with saliva at the bite site. Tick salivary glands produce complex cocktails of bioactive molecules that facilitate blood feeding and pathogen transmission by modulating host hemostasis, pain/itch responses, wound healing, and both innate and adaptive immunity. In this study, we utilized Illumina Next Generation Sequencing to characterize the transcriptional immunoprofile of cutaneous immune responses to
MeSH term(s)	Animals ; Chemokines/metabolism ; Cytokines/metabolism ; Disease Models, Animal ; Encephalitis Viruses, Tick-Borne/genetics ; Encephalitis Viruses, Tick-Borne/immunology ; Encephalitis, Tick-Borne/immunology ; Encephalitis, Tick-Borne/transmission ; Female ; Flavivirus/immunology ; Flavivirus/pathogenicity ; Gene Expression/immunology ; High-Throughput Nucleotide Sequencing ; Histocompatibility Antigens Class II/immunology ; Host-Parasite Interactions/immunology ; Immunohistochemistry ; Ixodes/immunology ; Mice ; Mice, Inbred BALB C ; Neutrophils/immunology ; Skin/immunology ; Skin/pathology ; Tick Bites/immunology
Chemical Substances	Chemokines ; Cytokines ; Histocompatibility Antigens Class II
Language	English
Publishing date	2017-12-01
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2619676-1
ISSN	2235-2988 ; 2235-2988
ISSN (online)	2235-2988
ISSN	2235-2988
DOI	10.3389/fcimb.2017.00494
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Article ; Online: Early immunologic events at the tick-host interface.

Heinze, Dar M / Carmical, J Russ / Aronson, Judith F / Thangamani, Saravanan

PloS one

2012 Volume 7, Issue 10, Page(s) e47301

Abstract: Ixodes species ticks are competent vectors of tick-borne viruses including tick-borne encephalitis and Powassan encephalitis. Tick saliva has been shown to facilitate and enhance viral infection. This likely occurs by saliva-mediated modulation of host ... ...

Abstract	Ixodes species ticks are competent vectors of tick-borne viruses including tick-borne encephalitis and Powassan encephalitis. Tick saliva has been shown to facilitate and enhance viral infection. This likely occurs by saliva-mediated modulation of host responses into patterns favorable for viral infection and dissemination. Because of the rapid kinetics of tick-borne viral transmission, this modulation must occur as early as tick attachment and initiation of feeding. In this study, cutaneous bite-site lesions were analyzed using Affymetrix mouse genome 430A 2.0 arrays and histopathology at 1, 3, 6, and 12 hours after uninfected Ixodes scapularis nymphal tick attachment. At 1 and 3 hrs after attachment, the gene expression profile is markedly different than at later time points. Upregulated gene ontology term clusters enriched at 1 and 3 hrs were related to post-translational modification. At 6 and 12 hrs, cytoskeletal rearrangements, DNA replication/cell division, inflammation, and chemotaxis were prominent clusters. At 6 and 12 hrs, extracellular matrix, signaling, and DNA binding clusters were downregulated. Histopathological analysis shows minimal inflammation at 1 and 3 hrs but an appreciable neutrophil infiltrate at 6 and 12 hrs. In addition, putative hyperemia, localized necrosis, and increased ECM deposition were identified. Putting the gene expression and histopathology analysis together suggests early tick feeding is characterized by modulation of host responses in resident cells that merges into a nascent, neutrophil-driven immune response by 12 hrs post-attachment.
MeSH term(s)	Animals ; DNA Replication/genetics ; Encephalitis, Tick-Borne/immunology ; Encephalitis, Tick-Borne/transmission ; Encephalitis, Tick-Borne/virology ; Host-Parasite Interactions/immunology ; Insect Vectors/immunology ; Insect Vectors/virology ; Ixodes/immunology ; Ixodes/virology ; Mice ; Nymph/immunology ; Saliva/immunology ; Saliva/virology ; Tick Infestations/immunology ; Transcriptome/immunology
Language	English
Publishing date	2012-10-15
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0047301
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Article ; Online: Transcriptional profiling of the murine cutaneous response during initial and subsequent infestations with Ixodes scapularis nymphs

Heinze Dar M / Wikel Stephen K / Thangamani Saravanan / Alarcon-Chaidez Francisco J

Parasites & Vectors, Vol 5, Iss 1, p

2012 Volume 26

Abstract: Abstract Background Ixodes scapularis ticks are hematophagous arthropods capable of transmitting many infectious agents to humans. The process of blood feeding is an extended and continuous interplay between tick and host responses. While this process ... ...

Abstract	Abstract Background Ixodes scapularis ticks are hematophagous arthropods capable of transmitting many infectious agents to humans. The process of blood feeding is an extended and continuous interplay between tick and host responses. While this process has been studied extensively in vitro , no global understanding of the host response to ticks has emerged. Methods To address this issue, we used PCR-arrays to measure skin-specific expression of 233 discrete genes at 8 time points during primary and secondary infestations of mice with pathogen-free I. scapularis nymphs. Selected results were then validated at the mRNA and protein levels by additional real-time PCR and bioplex assay. Results Primary infestation was characterized by the late induction of an innate immune response. Lectin pattern recognition receptors, cytokines, and chemokines were upregulated consistent with increased neutrophil and macrophage migration. Gene ontology and pathway analyses of downregulated genes suggested inhibition of gene transcription and Th17 immunity. During the secondary infestation, additional genes were modulated suggesting a broader involvement of immune cells including CD8 and CD4 positive T lymphocytes. The cytokine response showed a mixed Th1/Th2 profile with a potential for T regulatory cell activity. Key gene ontology clusters observed during the secondary infestation were cell migration and activation. Matrix metalloproteinases were upregulated, apoptosis-related genes were differentially modulated, and immunoreceptor signaling molecules were upregulated. In contrast, transcripts related to mitogenic, WNT, Hedgehog, and stress pathways were downregulated. Conclusions Our results support a model of tick feeding where lectin pattern recognition receptors orchestrate an innate inflammatory response during primary infestation that primes a mixed Th1/Th2 response upon secondary exposure. Tick feeding inhibits gene transcription and Th17 immunity. Salivary molecules may also inhibit upregulation of mitogenic, WNT, Hedgehog, and stress pathways and enhance the activity of T regulatory cells, production of IL-10, and suppressors of cytokine signaling molecules (SOCS). This study provides the first comprehensive transcriptional analysis of the murine host response at the I. scapularis bite site and suggests both a potential model of the host cutaneous response and candidate genes for further description and investigation.
Keywords	Tick(s) ; Ixodes scapularis ; Skin ; Cutaneous response ; Tick-host interface ; Gene expression profiling ; Microbiology ; QR1-502 ; Science ; Q ; DOAJ:Microbiology ; DOAJ:Biology ; DOAJ:Biology and Life Sciences ; Infectious and parasitic diseases ; RC109-216 ; Internal medicine ; RC31-1245 ; Medicine ; R ; DOAJ:Internal medicine ; DOAJ:Medicine (General) ; DOAJ:Health Sciences
Subject code	570
Language	English
Publishing date	2012-02-01T00:00:00Z
Publisher	BioMed Central
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Transcriptional profiling of the murine cutaneous response during initial and subsequent infestations with Ixodes scapularis nymphs

Heinze, Dar M / Alarcon-Chaidez, Francisco J / Thangamani, Saravanan / Wikel, Stephen K

Parasites & vectors. 2012 Dec., v. 5, no. 1

2012

Abstract: BACKGROUND: Ixodes scapularis ticks are hematophagous arthropods capable of transmitting many infectious agents to humans. The process of blood feeding is an extended and continuous interplay between tick and host responses. While this process has been ... ...

Abstract	BACKGROUND: Ixodes scapularis ticks are hematophagous arthropods capable of transmitting many infectious agents to humans. The process of blood feeding is an extended and continuous interplay between tick and host responses. While this process has been studied extensively in vitro, no global understanding of the host response to ticks has emerged. METHODS: To address this issue, we used PCR-arrays to measure skin-specific expression of 233 discrete genes at 8 time points during primary and secondary infestations of mice with pathogen-free I. scapularis nymphs. Selected results were then validated at the mRNA and protein levels by additional real-time PCR and bioplex assay. RESULTS: Primary infestation was characterized by the late induction of an innate immune response. Lectin pattern recognition receptors, cytokines, and chemokines were upregulated consistent with increased neutrophil and macrophage migration. Gene ontology and pathway analyses of downregulated genes suggested inhibition of gene transcription and Th17 immunity. During the secondary infestation, additional genes were modulated suggesting a broader involvement of immune cells including CD8 and CD4 positive T lymphocytes. The cytokine response showed a mixed Th1/Th2 profile with a potential for T regulatory cell activity. Key gene ontology clusters observed during the secondary infestation were cell migration and activation. Matrix metalloproteinases were upregulated, apoptosis-related genes were differentially modulated, and immunoreceptor signaling molecules were upregulated. In contrast, transcripts related to mitogenic, WNT, Hedgehog, and stress pathways were downregulated. CONCLUSIONS: Our results support a model of tick feeding where lectin pattern recognition receptors orchestrate an innate inflammatory response during primary infestation that primes a mixed Th1/Th2 response upon secondary exposure. Tick feeding inhibits gene transcription and Th17 immunity. Salivary molecules may also inhibit upregulation of mitogenic, WNT, Hedgehog, and stress pathways and enhance the activity of T regulatory cells, production of IL-10, and suppressors of cytokine signaling molecules (SOCS). This study provides the first comprehensive transcriptional analysis of the murine host response at the I. scapularis bite site and suggests both a potential model of the host cutaneous response and candidate genes for further description and investigation.
MeSH term(s)	Animals ; Cell Movement ; Cytokines/analysis ; Down-Regulation/genetics ; Female ; Gene Expression Profiling ; Gene Expression Regulation/genetics ; Host-Pathogen Interactions/physiology ; Humans ; Immunity, Innate ; Insect Bites and Stings ; Ixodes/genetics/immunology ; Mice ; Mice, Inbred BALB C ; Nymph/genetics/immunology ; RNA, Messenger/genetics ; Signal Transduction ; Skin/parasitology ; Specific Pathogen-Free Organisms ; Tick Infestations/immunology/parasitology ; Time Factors ; Up-Regulation/genetics
Keywords	cell movement ; chemokines ; gene expression regulation ; genes ; humans ; inflammation ; innate immunity ; interleukin-10 ; Ixodes scapularis ; lectins ; macrophages ; messenger RNA ; metalloproteinases ; mice ; models ; nymphs ; parasitism ; pathogens ; quantitative polymerase chain reaction ; receptors ; secondary contact ; tick infestations ; ticks ; T-lymphocytes ; transcription (genetics)
Language	English
Dates of publication	2012-12
Size	p. 26.
Publishing place	BioMed Central
Document type	Article
ZDB-ID	2409480-8
ISSN	1756-3305
ISSN	1756-3305
DOI	10.1186/1756-3305-5-26
Database	NAL-Catalogue (AGRICOLA)

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Article: Elevated Humoral Immune Response to SARS-CoV-2 at High Altitudes Revealed by an Anti-RBD "

Tomas-Grau, Rodrigo Hernán / Ploper, Diego / Ávila, César Luis / Vera Pingitore, Esteban / Maldonado Galdeano, Carolina / Chaves, Silvina / Socias, Sergio Benjamín / Stagnetto, Agustín / Navarro, Silvia Adriana / Chahla, Rossana Elena / Aguilar López, Mónica / Llapur, Conrado Juan / Aznar, Patricia / Alcorta, María Elena / Costas, Dardo / Flores, Isolina / Heinze, Dar / Apfelbaum, Gabriela / Mostoslavsky, Raul /

Mostoslavsky, Gustavo / Cazorla, Silvia Inés / Perdigón, Gabriela Del Valle / Chehín, Rosana

Frontiers in medicine

2021 Volume 8, Page(s) 720988

Abstract: The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has caused a global pandemic with dramatic health and socioeconomic consequences. The Coronavirus Disease 2019 (COVID-19) challenges health systems to quickly respond by developing new ... ...

Abstract	The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has caused a global pandemic with dramatic health and socioeconomic consequences. The Coronavirus Disease 2019 (COVID-19) challenges health systems to quickly respond by developing new diagnostic strategies that contribute to identify infected individuals, monitor infections, perform contact-tracing, and limit the spread of the virus. In this brief report, we developed a highly sensitive, specific, and precise "
Language	English
Publishing date	2021-10-14
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2775999-4
ISSN	2296-858X
ISSN	2296-858X
DOI	10.3389/fmed.2021.720988
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Article ; Online: Transcriptional profiling of the murine cutaneous response during initial and subsequent infestations with Ixodes scapularis nymphs.

Heinze, Dar M / Wikel, Stephen K / Thangamani, Saravanan / Alarcon-Chaidez, Francisco J

Parasites & vectors

2012 Volume 5, Page(s) 26

Abstract: Background: Ixodes scapularis ticks are hematophagous arthropods capable of transmitting many infectious agents to humans. The process of blood feeding is an extended and continuous interplay between tick and host responses. While this process has been ... ...

Abstract	Background: Ixodes scapularis ticks are hematophagous arthropods capable of transmitting many infectious agents to humans. The process of blood feeding is an extended and continuous interplay between tick and host responses. While this process has been studied extensively in vitro, no global understanding of the host response to ticks has emerged. Methods: To address this issue, we used PCR-arrays to measure skin-specific expression of 233 discrete genes at 8 time points during primary and secondary infestations of mice with pathogen-free I. scapularis nymphs. Selected results were then validated at the mRNA and protein levels by additional real-time PCR and bioplex assay. Results: Primary infestation was characterized by the late induction of an innate immune response. Lectin pattern recognition receptors, cytokines, and chemokines were upregulated consistent with increased neutrophil and macrophage migration. Gene ontology and pathway analyses of downregulated genes suggested inhibition of gene transcription and Th17 immunity. During the secondary infestation, additional genes were modulated suggesting a broader involvement of immune cells including CD8 and CD4 positive T lymphocytes. The cytokine response showed a mixed Th1/Th2 profile with a potential for T regulatory cell activity. Key gene ontology clusters observed during the secondary infestation were cell migration and activation. Matrix metalloproteinases were upregulated, apoptosis-related genes were differentially modulated, and immunoreceptor signaling molecules were upregulated. In contrast, transcripts related to mitogenic, WNT, Hedgehog, and stress pathways were downregulated. Conclusions: Our results support a model of tick feeding where lectin pattern recognition receptors orchestrate an innate inflammatory response during primary infestation that primes a mixed Th1/Th2 response upon secondary exposure. Tick feeding inhibits gene transcription and Th17 immunity. Salivary molecules may also inhibit upregulation of mitogenic, WNT, Hedgehog, and stress pathways and enhance the activity of T regulatory cells, production of IL-10, and suppressors of cytokine signaling molecules (SOCS). This study provides the first comprehensive transcriptional analysis of the murine host response at the I. scapularis bite site and suggests both a potential model of the host cutaneous response and candidate genes for further description and investigation.
MeSH term(s)	Animals ; Cell Movement ; Cytokines/analysis ; Down-Regulation/genetics ; Female ; Gene Expression Profiling ; Gene Expression Regulation/genetics ; Host-Pathogen Interactions/physiology ; Humans ; Immunity, Innate ; Insect Bites and Stings ; Ixodes/genetics ; Ixodes/immunology ; Mice ; Mice, Inbred BALB C ; Nymph/genetics ; Nymph/immunology ; RNA, Messenger/genetics ; Signal Transduction ; Skin/parasitology ; Specific Pathogen-Free Organisms ; Tick Infestations/immunology ; Tick Infestations/parasitology ; Time Factors ; Up-Regulation/genetics
Chemical Substances	Cytokines ; RNA, Messenger
Language	English
Publishing date	2012-02-06
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2409480-8
ISSN	1756-3305 ; 1756-3305
ISSN (online)	1756-3305
ISSN	1756-3305
DOI	10.1186/1756-3305-5-26
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Murine cutaneous responses to the rocky mountain spotted fever vector, Dermacentor andersoni, feeding.

Heinze, Dar M / Carmical, J Russ / Aronson, Judith F / Alarcon-Chaidez, Franscisco / Wikel, Stephen / Thangamani, Saravanan

Frontiers in microbiology

2014 Volume 5, Page(s) 198

Abstract: Tick salivary glands produce complex cocktails of bioactive molecules that facilitate blood feeding and pathogen transmission by modulating host hemostasis, pain/itch responses, wound healing, and both innate and adaptive immunity. In this study, ... ...

Abstract	Tick salivary glands produce complex cocktails of bioactive molecules that facilitate blood feeding and pathogen transmission by modulating host hemostasis, pain/itch responses, wound healing, and both innate and adaptive immunity. In this study, cutaneous responses at Dermacentor andersoni bite-sites were analyzed using Affymetrix mouse genome arrays and histopathology at 12, 48, 96 and 120 h post- infestation (hpi) during primary infestations and 120 hpi during secondary infestations. The microarray data suggests: (1) chemotaxis of neutrophils, monocytes, and other cell types; (2) production and scavenging of reactive oxygen species; and, (3) keratin- based wound healing responses. Histological analysis supported the microarray findings. At 12 hpi, a mild inflammatory infiltrate was present in the dermis, especially concentrated at the junction between dermal connective tissue and underlying adipose tissue. A small lesion was located immediately under the hypostome and likely represents the feeding "pool." Surprisingly, at 48 hpi, the number of inflammatory cells had not increased from 12 hpi, perhaps mirroring the reduction in gene expression seen at this time point. The feeding lesion is very well defined, and extravasated erythrocytes are readily evident around the hypostome. By 96 hpi, the inflammatory infiltrate has increased dramatically and the feeding lesion appears to have moved deeper into the dermis. At 120 hpi, most of the changes at 96 hpi are intensified. The infiltrate is very dense, the epidermis is markedly thickened, the feeding lesion is poorly defined and the dermal tissue near the hypostome appears to be loosing its normal architecture. In conclusion, during D. andersoni feeding infiltration of inflammatory cells increases across time concurrent with significant changes in the epidermal and dermal compartments near the feeding tick. The importance of changes in the epidermal layer in the host response to ticks is not known, however, it is possible the host attempts to "slough off" the tick by greatly increasing epithelial cell replication.
Language	English
Publishing date	2014-05-07
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2587354-4
ISSN	1664-302X
ISSN	1664-302X
DOI	10.3389/fmicb.2014.00198
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Article: Detection of Rickettsia amblyommii in ticks collected from Missouri, USA.

Hermance, Meghan / Dos Santos, Rodrigo I Marques / Heinze, Dar / Hausser, Nicole / Bouyer, Donald H / Thangamani, Saravanan

Emerging microbes & infections

2014 Volume 3, Issue 5, Page(s) e34

Language	English
Publishing date	2014-05
Publishing country	United States
Document type	Journal Article
ZDB-ID	2681359-2
ISSN	2222-1751
ISSN	2222-1751
DOI	10.1038/emi.2014.31
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