Immunity-and-Matrix-Regulatory Cells Derived from Human Embryonic Stem Cells Safely and Effectively Treat Mouse Lung Injury and Fibrosis

AbstractLung injury and fibrosis represent the most significant outcomes of severe and acute lung disorders, including COVID-19. However, there are still no effective drugs to treat lung injury and fibrosis. In this study, we report the generation of clinical-grade human embryonic stem cells (hESCs)-derived immunity- and matrix-regulatory cells (IMRCs) produced under good manufacturing practice (GMP) requirements, that can treat lung injury and fibrosis in vivo. We generate IMRCs by sequentially differentiating hESCs with serum-free reagents. IMRCs possess a unique gene expression profile distinct from umbilical cord mesenchymal stem cells (UCMSCs), such as higher levels of proliferative, immunomodulatory and anti-fibrotic genes. Moreover, intravenous delivery of IMRCs inhibits both pulmonary inflammation and fibrosis in mouse models of lung injury, and significantly improves the survival rate of the recipient mice in a dose-dependent manner, likely through paracrine regulatory mechanisms. IMRCs are superior to both primary UCMSCs and FDA-approved pirfenidone, with an excellent efficacy and safety profile in mice and monkeys. In light of public health crises involving pneumonia, acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), our findings suggest that IMRCs are ready for clinical trials on lung disorders.

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Immunity-and-matrix-regulatory cells derived from human embryonic stem cells safely and effectively treat mouse lung injury and fibrosis

Cell Research ◽

10.1038/s41422-020-0354-1 ◽

2020 ◽

Vol 30 (9) ◽

pp. 794-809 ◽

Cited By ~ 4

Author(s):

Jun Wu ◽

Dingyun Song ◽

Zhongwen Li ◽

Baojie Guo ◽

Yani Xiao ◽

...

Keyword(s):

Stem Cells ◽

Embryonic Stem Cells ◽

Lung Injury ◽

Human Embryonic Stem Cells ◽

Embryonic Stem ◽

Mouse Lung ◽

Regulatory Cells

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Faculty Opinions recommendation of Liver X receptors and oxysterols promote ventral midbrain neurogenesis in vivo and in human embryonic stem cells.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1165297.628246 ◽

2009 ◽

Author(s):

Magdalena Goetz

Keyword(s):

Stem Cells ◽

Embryonic Stem Cells ◽

Human Embryonic Stem Cells ◽

Embryonic Stem ◽

Liver X Receptors ◽

Ventral Midbrain ◽

X Receptors

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In vivo Differentiation of Human Embryonic Stem Cells

Human Embryonic Stem Cells ◽

10.1002/9780470511619.ch9 ◽

2007 ◽

pp. 121-147

Author(s):

Scott A. Noggle ◽

Francesca M. Spagnoli ◽

Ali H. Brivanlou

Keyword(s):

Stem Cells ◽

Embryonic Stem Cells ◽

Human Embryonic Stem Cells ◽

Embryonic Stem ◽

In Vivo Differentiation

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304 THE DEVELOPMENTAL TOXICITY EVALUATION OF 5-FLUOROURACIL AND INDOMETHACIN IN HUMAN EMBRYONIC STEM CELLS

Reproduction Fertility and Development ◽

10.1071/rdv25n1ab304 ◽

2013 ◽

Vol 25 (1) ◽

pp. 299

Author(s):

E. M. Jung ◽

E. B. Jeung

Keyword(s):

Stem Cells ◽

Transcription Factors ◽

Embryonic Stem Cells ◽

Human Embryonic Stem Cells ◽

Developmental Process ◽

Developmental Toxicity ◽

Embryonic Stem ◽

Surface Markers ◽

Dependent Manner ◽

Undifferentiated Hesc

Embryonic stem cells have pluripotency and differentiate into and constitute the cells and tissues of our body. In this study, using human embryonic stem cells (hESC), we evaluated novel methods for screening toxicological chemicals during developmental process. We elucidated developmental toxicity of two well-known chemicals, 5-fluorouracil (5-FU) and indomethacin (Indo) in hESC. The undifferentiated hESC were treated with the chemicals (10–4 to 104 µM of 5-FU and Indo) in a dose-dependent manner during 1 to 3 days. Surface markers (SSEA-4, TRA-1-60, and TRA-1-81) expressed only in undifferentiated hESC were monitored by immunocytochemistry to ensure the characterisation of undifferentiated hESC. Moreover, expression of embryonic stem cell-specific genes was assessed with real-time PCR after treatment of 5-FU and Indo (10–2, 100, and102 µM of 5-FU and Indo). The expression of surface markers was not significantly affected by treatment of 5-FU and Indo. The expression of transcription factors (Oct-4, Sox-2, Nanog, and hTERT) was significantly decreased by high concentrations of 5-FU and Indo (102 µM). However, no difference was observed in treatment of low concentration of 5-FU and Indo (10–2 µM). Taken together, these results suggest that 5-FU and Indo have cytotoxic effects, and modulate the expression of transcription factors that have pivotal roles in undifferentiated hESC. Therefore, we suggest that hESC may have potential to test toxicity of chemicals during embryonic developmental stage.

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100. IN VIVO DIFFERENTIATION OF HUMAN EMBRYONIC STEM CELLS TO UTERINE TISSUE

Reproduction Fertility and Development ◽

10.1071/srb09abs100 ◽

2009 ◽

Vol 21 (9) ◽

pp. 19

Author(s):

L. Ye ◽

R. Mayberry ◽

E. Stanley ◽

A. Elefanty ◽

C. Gargett

Keyword(s):

Stem Cells ◽

Embryonic Stem Cells ◽

Epithelial Cells ◽

Human Embryonic Stem Cells ◽

Embryonic Stem ◽

Mesenchymal Cells ◽

Neonatal Mouse ◽

Endometrial Tissue ◽

Human Epithelial Cells

The endometrium undergoes cyclic regeneration. This regeneration has been attributed to adult stem progenitor cells and developmental mechanisms [1, 2]. A better understanding of human endometrial development may shed light on the mechanisms involved in endometrial regeneration and on early origins of adult endometrial disease. The lack of human fetal endometrial tissue has impeded research in early human endometrial development. We hypothesized that directed differentiation of human embryonic stem cells (hESC) to human endometrial tissue by neonatal mouse uterine mesenchyme represents a novel system to study early development of human endometrium. Recent studies have shown that the neonatal mouse uterine mesenchyme is extremely inductive and undergoes reciprocal signalling with human endometrial epithelial cells [3]. Our aim is to establish a xenograft tissue recombination protocol based on a model for human prostate tissue differentiation using hESC [4]. Our method involved formation of embryoid body (EB) with GFP labelled hESC (ENVY) [5] for recombination with 2x0.5mm pieces of epithelial-free uterine mesenchyme from postnatal day 1 mice. Upon fusion in culture, the recombinant tissue is grafted under the kidney capsule of NOD/SCID mice for 4-12 weeks and monitored by in-vivo imaging. Immunohistochemical analysis of recombinant grafts 4 weeks post transplantation (n=4) revealed immature CK8+CK18+Hoxa10+ human epithelial cells surrounded by mouse mesenchymal cells suggesting differentiation of hESC to epithelial cells possibly of endometrial lineage. The ER+PR+SMA+Hoxa10+ mouse mesenchymal cells surrounding human glands differentiated into SMA+ cells possibly via reciprocal signalling from human epithelial cells. At 8 weeks, we found several CK18+/Hoxa10+ human glands co-expressing CA125. These glands are supported by Hoxa10+ human stromal cells. Further experiments are underway to induce the expression of ER and PR in Hoxa10+ epithelial cells which will be crucial in revealing their endometrial lineage.

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In Vitro Differentiation and In Vivo Mineralization of Osteogenic Cells Derived from Human Embryonic Stem Cells

Tissue Engineering ◽

10.1089/ten.2004.10.1518 ◽

2004 ◽

Vol 10 (9-10) ◽

pp. 1518-1525 ◽

Cited By ~ 187

Author(s):

Robert C. Bielby ◽

Aldo R. Boccaccini ◽

Julia M. Polak ◽

Lee D.K. Buttery

Keyword(s):

Stem Cells ◽

Embryonic Stem Cells ◽

Human Embryonic Stem Cells ◽

Embryonic Stem ◽

In Vitro Differentiation ◽

Osteogenic Cells

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A protocol for the differentiation of human embryonic stem cells into dopaminergic neurons using only chemically defined human additives: Studies in vitro and in vivo

Brain Research ◽

10.1016/j.brainres.2006.10.022 ◽

2007 ◽

Vol 1127 ◽

pp. 19-25 ◽

Cited By ~ 80

Author(s):

Lorraine Iacovitti ◽

Angela E. Donaldson ◽

Cheryl E. Marshall ◽

Sokreine Suon ◽

Ming Yang

Keyword(s):

Stem Cells ◽

Embryonic Stem Cells ◽

Human Embryonic Stem Cells ◽

Dopaminergic Neurons ◽

Embryonic Stem

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Human embryonic stem cells differentiate into a homogeneous population of natural killer cells with potent in vivo antitumor activity

Blood ◽

10.1182/blood-2008-06-165225 ◽

2009 ◽

Vol 113 (24) ◽

pp. 6094-6101 ◽

Cited By ~ 130

Author(s):

Petter S. Woll ◽

Bartosz Grzywacz ◽

Xinghui Tian ◽

Rebecca K. Marcus ◽

David A. Knorr ◽

...

Keyword(s):

Stem Cells ◽

Embryonic Stem Cells ◽

Nk Cells ◽

Natural Killer ◽

Human Embryonic Stem Cells ◽

Embryonic Stem ◽

Human Tumor ◽

Homogeneous Population ◽

Tumor Clearance

Abstract Natural killer (NK) cells serve as important effectors for antitumor immunity, and CD56+CD45+ NK cells can be routinely derived from human embryonic stem cells (hESCs). However, little is know about the ability of hESC-derived NK cells to mediate an effective in vivo antitumor response. Using bioluminescent imaging, we now demonstrate that H9 line hESC-derived NK cells mediate effective clearance of human tumor cells in vivo. In addition to increased in vitro killing of diverse tumor targets, the in vivo tumor clearance by H9 hESC-derived NK cells was more effective compared with NK cells derived from umbilical cord blood (UCB). Phenotypic analysis demonstrates the hESC-derived NK cells are uniformly CD94+CD117low/−, an NK-cell population characterized by potent cytolytic activity and thus more competent to mediate tumor clearance. These studies demonstrate that hESCs provide an important model to study human lymphocyte development and may serve as a novel source for antitumor immunotherapy.

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Generation of T Cells from Human Embryonic Stem Cells.

Blood ◽

10.1182/blood.v112.11.1527.1527 ◽

2008 ◽

Vol 112 (11) ◽

pp. 1527-1527

Author(s):

Frank Timmermans ◽

Imke Velghe ◽

Lieve Van Walleghem ◽

Magda De Smedt ◽

Stefanie Van Coppernolle ◽

...

Keyword(s):

Stem Cells ◽

T Cells ◽

Embryonic Stem Cells ◽

Human Embryonic Stem Cells ◽

Early Stage ◽

Embryonic Stem ◽

Hesc Line ◽

Double Positive

Abstract Background: Human embryonic stem cells (hESC) are derived from early stage blastocysts and are characterized by the ability to both self-renew and to generate differentiated functional cell types. One of the major challenges in the field of hESC research, is to set up a culture system that drives hESC down a particular lineage fate. To date, studies reporting hematopoietic development have not provided evidence on the differentiation capacity of hESC into T lineage cells in vitro. Material and Methods: hESC line H1 (National Institutes of Health [NIH] code: WA01), Wisconson, Madison, USA) was used (Passage 30–60) in all experiments. The hESC line was kept in an undifferentiated state on MEFs as previously described. OP9 cells and OP9 cells that express high levels of the Notch ligand Delta-like 1 (OP9-DLL1, a gift from J. C. Zuniga-Pflücker, University of Toronto, Canada) were cultured as previously described in MEM-α with 20 % FCS. Results: Our data show that T cells can be generated in vitro from hESC in a robust and highly reproducible manner using the sequential exposure of hESC to the murine OP9 cell line and OP9-DLL1. On OP9 stromal layers, a CD34highCD43dim hematopoietic precursor population is generated that is confined to vascular-like structures, reminiscent of blood islands that emerge during in vivo embryonic development. This precursor population becomes T lineage committed when exposed to OP9-DLL1 monolayers, passing sequentially through a CD34+CD7+ phenotype, a CD4+CD8+ double positive intermediate stage and eventually differentiates into a mature T cells. Polyclonal T cells are generated, cell receptor (TCR) alpha-beta and TCRgamma-delta which are functional based on proliferative capacity and production of cytokines after TCR crosslinking. Conclusion: We show that mature and functional T cells can be generated from hESC using well defined in vitro conditions. This protocol in combination with the recently described induced pluripotent cells may find clinical applicability in tumor immunology.

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