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Highly Efficient Reprogramming to Pluripotency and Directed Differentiation of Human Cells with Synthetic Modified mRNA
Open accessAbstract
Clinical application of induced pluripotent stem cells (iPSCs) is limited by the low efficiency of iPSC derivation and the fact that most protocols modify the genome to effect cellular reprogramming. Moreover, safe and effective means of directing the fate of patient-specific iPSCs toward clinically useful cell types are lacking. Here we describe a simple, nonintegrating strategy for reprogramming cell fate based on administration of synthetic mRNA modified to overcome innate antiviral responses. We show that this approach can reprogram multiple human cell types to pluripotency with efficiencies that greatly surpass established protocols. We further show that the same technology can be used to efficiently direct the differentiation of RNA-induced pluripotent stem cells (RiPSCs) into terminally differentiated myogenic cells. This technology represents a safe, efficient strategy for somatic cell reprogramming and directing cell fate that has broad applicability for basic research, disease modeling, and regenerative medicine.
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“Using enhanced green fluorescent protein mRNA, Rossi and colleagues confirmed that nucleoside modifications can strongly enhance protein expression and suppress cytokine secretion.”
From Sequence-engineered mRNA without chemical nucleoside modifications enables an effective protein therapy in large animals (2015) · cites this paper as [24]
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“Our work principally confirms that conventional unmodified mRNAs are inferior to molecules harboring specific nucleoside modifications as suggested by various recent reports,23,24,25,26,27 however, the picture changes dramatically with a sophisticated sequence-engineering.”
From Sequence-engineered mRNA without chemical nucleoside modifications enables an effective protein therapy in large animals (2015) · cites this paper as [24]
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“Second, we studied the efficiency and robustness of cellular reprogramming of human fibroblasts to iPSCs with mRNA-encoded transcription factors, which is considered to benefit from prolonged mRNA stability.17,51”
From Improving mRNA-Based Therapeutic Gene Delivery by Expression-Augmenting 3′ UTRs Identified by Cellular Library Screening (2019) · cites this paper as [51]
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Metadata
- Authors
- Warren, L., Manos, P. D., Ahfeldt, T., Loh, Y.-H., Li, H., Lau, F., Ebina, W., Mandal, P. K., Smith, Z. D., Meissner, A., Daley, G. Q., Brack, A. S., Collins, J. J., Cowan, C., Schlaeger, T. M., & Rossi, D. J.
- Affiliations
- Boston Children's Hospital (US)
- Harvard University (US)
- Boston University (US)
- Broad Institute (US)
- Brigham and Women's Hospital (US)
- Corresponding author
- Rossi, Derrick J.
- ORCID
- Venue
- Cell Stem Cell
- Publisher
- Elsevier BV
- Published
- 2010-11
- Volume
- 7
- Issue
- 5
- Pages
- 618-630
- ISSN
- 1875-9777 (ISSN-L)
- 1934-5909
- PMC
- PMC3656821
- OpenAlex
- W2098597036
- Cited by
- 2,662
- References
- 55
- Citations by year
- 2026: 74 · 2025: 67 · 2024: 89 · 2023: 81 · 2022: 109 · 2021: 153 · 2020: 148 · 2019: 130 · 2018: 178 · 2017: 167 · 2016: 201 · 2015: 208 · 2014: 235 · 2013: 264 · 2012: 288
- FWCI
- 106.76
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 989 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell stem cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- Funders
- Howard Hughes Medical Institute
- National Heart, Lung, and Blood Institute (U01HL100001)
- National Institute of Dental and Craniofacial Research (RL1DE01902, RL1DE019021)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Keywords
- synthetic mRNA, somatic cell reprogramming, pluripotency, directed differentiation, myogenesis, antiviral response, disease modeling, regenerative medicine
- MeSH terms
- Cell Differentiation, Cells, Cultured, Humans, RNA, Messenger, Cell Lineage, Induced Pluripotent Stem Cells, Cellular Reprogramming
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