mRNA-mediated glycoengineering ameliorates deficient homing of human stem cell–derived hematopoietic progenitors

Lee, Jungmin; Dykstra, Brad; Spencer, Joel A.; Kenney, Laurie L.; Greiner, Dale L.; Shultz, Leonard D.; Brehm, Michael A.; Lin, Charles P.; Sackstein, Robert; Rossi, Derrick J.

doi:10.1172/jci92030

Cited by 25 publications

(29 citation statements)

References 17 publications

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“…1). Our results prove the concept of this approach and significantly increase protein production compared to the UTRs reported in the literatures 12,[16][17][18] . Lastly, a series of potential SARS-CoV-2 antigens are visualized via fluorescent imaging in both cell and animal models, which may serve as vaccine candidates for the clinical trials.…”

Section: Introductionsupporting

confidence: 84%

“…Through the comprehensive UTR engineering, the optimal UTRs was identified as NCA-7d as the 5' UTR and S27a plus a functional motif R3U as the 3' UTR (named as NASAR). After several rounds of design and validation of UTRs, we then compared NASAR with S27a-45, the starting point of endogenous gene together with two additional control UTRs (MOD1 and MOD2) in the literature 16,17 . NASAR was over 10-fold more potent than S27a-45, 4 to 7-fold better than CYBA or AG+G, and up to 2-fold superior to MOD1 and MOD2 in cell lines and primary cells ( Fig.…”

Section: Optimization Of 3' Utr With Integrated Motifsmentioning

confidence: 99%

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Leveraging mRNAs sequences to express SARS-CoV-2 antigens in vivo

Zeng

Hou

Yan

et al. 2020

Preprint

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SARS-CoV-2 has rapidly become a pandemic worldwide; therefore, an effective vaccine is urgently needed. Recently, messenger RNAs (mRNAs) have emerged as a promising platform for vaccination. Here, we systematically investigated the untranslated regions (UTRs) of mRNAs in order to enhance protein production. Through a comprehensive analysis of endogenous gene expression and de novo design of UTRs, we identified the optimal combination of 5' and 3' UTR, termed as NASAR, which was five to ten-fold more efficient than the tested endogenous UTRs. More importantly, NASAR mRNAs delivered by lipid-derived nanoparticles showed dramatic expression of potential SARS-CoV-2 antigens both in vitro and in vivo. These NASAR mRNAs merit further development as alternative SARS-CoV-2 vaccines.was not certified by peer review)

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Section: Introductionsupporting

confidence: 84%

Section: Optimization Of 3' Utr With Integrated Motifsmentioning

confidence: 99%

Leveraging mRNAs sequences to express SARS-CoV-2 antigens in vivo

Zeng

Hou

Yan

et al. 2020

Preprint

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“…The development of humanized mouse models to study HLA-restricted tumor antigen-specific T-cell responses is underway and will require the complete MHC matching between engrafting HPSCs and the tumor, as well as the use of HLA-expressing NSG mice for human T-cell development ( 41 ). Recent advancements in generating human HPSCs from induced pluripotent stem cells or embryonic stem cells will facilitate the generation of humanized Onco-HuNSG mice that are engrafted with autologous tumors and HPSCs in the future ( 42 ).…”

Section: Discussionmentioning

confidence: 99%

Humanized mice in studying efficacy and mechanisms of PD‐1‐targeted cancer immunotherapy

et al. 2018

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Establishment of an in vivo small animal model of human tumor and human immune system interaction would enable preclinical investigations into the mechanisms underlying cancer immunotherapy. To this end, nonobese diabetic (NOD).Cg-PrkdcscidIL2rgtm1Wjl/Sz (null; NSG) mice were transplanted with human (h)CD34+ hematopoietic progenitor and stem cells, which leads to the development of human hematopoietic and immune systems [humanized NSG (HuNSG)]. HuNSG mice received human leukocyte antigen partially matched tumor implants from patient-derived xenografts [PDX; non–small cell lung cancer (NSCLC), sarcoma, bladder cancer, and triple-negative breast cancer (TNBC)] or from a TNBC cell line-derived xenograft (CDX). Tumor growth curves were similar in HuNSG compared with nonhuman immune-engrafted NSG mice. Treatment with pembrolizumab, which targets programmed cell death protein 1, produced significant growth inhibition in both CDX and PDX tumors in HuNSG but not in NSG mice. Finally, inhibition of tumor growth was dependent on hCD8+ T cells, as demonstrated by antibody-mediated depletion. Thus, tumor-bearing HuNSG mice may represent an important, new model for preclinical immunotherapy research.—Wang, M., Yao, L.-C., Cheng, M., Cai, D., Martinek, J., Pan, C.-X., Shi, W., Ma, A.-H., De Vere White, R. W., Airhart, S., Liu, E. T., Banchereau, J., Brehm, M. A., Greiner, D. L., Shultz, L. D., Palucka, K., Keck, J. G. Humanized mice in studying efficacy and mechanisms of PD-1-targeted cancer immunotherapy.

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“…Previous studies assessing hPSC-HPC engraftment potential have reported low levels of human hematopoietic microchimerism in immunocompromised mouse BM 4 weeks or more post transplant ( Doulatov et al., 2013 , Doulatov et al., 2017 , Gori et al., 2015 , Lee et al., 2017 , Ramos-Mejia et al., 2014 , Ran et al., 2013 , Risueño et al., 2012 , Wang et al., 2005 ). Here, we reveal the previously unappreciated early transplantation failure of hPSC-HPCs in vivo that occurs within the first 24 hr, despite robust hematopoietic progenitor capacity detected for weeks in vitro .…”

Section: Introductionmentioning

confidence: 99%

“…However, given the scarcity of compatible donors against the number of patients in need ( Gratwohl et al., 2015 ), developing alternative sources of HSCs is paramount. While hematopoietic progenitor cells (HPCs) can readily be generated by human pluripotent stem cells (hPSCs) in vitro , they lack robust engraftment potential ( Gori et al., 2015 , Lee et al., 2017 , Ng et al., 2016 , Risueño et al., 2012 , Wang et al., 2005 ). Ectopic transcription factor (TF) expression has been used in attempts to induce bone marrow (BM) engraftment of hPSC-HPCs ( Doulatov et al., 2013 , Doulatov et al., 2017 , Ramos-Mejia et al., 2014 , Ran et al., 2013 , Wang et al., 2005 ).…”

Section: Introductionmentioning

confidence: 99%

CXCL12/CXCR4 Signaling Enhances Human PSC-Derived Hematopoietic Progenitor Function and Overcomes Early In Vivo Transplantation Failure

et al. 2018

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SummaryHuman pluripotent stem cells (hPSCs) generate hematopoietic progenitor cells (HPCs) but fail to engraft xenograft models used to detect adult/somatic hematopoietic stem cells (HSCs) from donors. Recent progress to derive hPSC-derived HSCs has relied on cell-autonomous forced expression of transcription factors; however, the relationship of bone marrow to transplanted cells remains unknown. Here, we quantified a failure of hPSC-HPCs to survive even 24 hr post transplantation. Across several hPSC-HPC differentiation methodologies, we identified the lack of CXCR4 expression and function. Ectopic CXCR4 conferred CXCL12 ligand-dependent signaling of hPSC-HPCs in biochemical assays and increased migration/chemotaxis, hematopoietic progenitor capacity, and survival and proliferation following in vivo transplantation. This was accompanied by a transcriptional shift of hPSC-HPCs toward somatic/adult sources, but this approach failed to produce long-term HSC xenograft reconstitution. Our results reveal that networks involving CXCR4 should be targeted to generate putative HSCs with in vivo function from hPSCs.

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mRNA-mediated glycoengineering ameliorates deficient homing of human stem cell–derived hematopoietic progenitors

Cited by 25 publications

References 17 publications

Leveraging mRNAs sequences to express SARS-CoV-2 antigens in vivo

Leveraging mRNAs sequences to express SARS-CoV-2 antigens in vivo

Humanized mice in studying efficacy and mechanisms of PD‐1‐targeted cancer immunotherapy

CXCL12/CXCR4 Signaling Enhances Human PSC-Derived Hematopoietic Progenitor Function and Overcomes Early In Vivo Transplantation Failure

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