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| Status |
Public on Aug 28, 2022 |
| Title |
Direct chemical reprogramming of human cord blood erythroblasts to induced megakaryocytes that produce platelets |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
The shortage of platelets is becoming increasingly prominent owing to their short shelf life, limited supply, and increasing demand in response to public health incidents. It is an attractive idea to obtain large numbers of transfusible megakaryocytes (MKs) and platelets from somatic cells via cell lineage reprogramming. However, generating human MKs from somatic cells using a pharmacological reprogramming approach has not been widely explored. Here, we report the successful generation of human induced MKs (iMKs) from cord blood erythroblasts (EBs) using a chemical reprogramming strategy with a combination of four small molecules (4M): Bix01294, RG108, VPA, and PD0325901. The iMKs exhibited the ability to produce proplatelets and release vital functional platelets in vitro, demonstrating their similarity to natural MKs. Importantly, after injection into mice, iMKs were able to mature and give rise to functional platelets that were incorporated into newly formed thrombi. The reprogramming process was carefully examined using single-cell RNA sequencing, which revealed an efficient, rapid, and successful cell fate conversion of EBs to iMKs by 4M via the intermediate state of bipotent precursors. Assay for transposase-accessible chromatin sequencing results indicated that 4M induced genome-wide chromatin remodeling during MK reprogramming from EBs. 4M drove the transition of the transcription factor gene network by downregulating the key erythroid transcription factor genes KLF1 and MYB and subsequently upregulating MK development-associated transcription factor genes, including FLI1 and MEIS1. This process eventually led human cord blood EBs to acquire the MK fate. Thus, our chemical reprogramming of cord blood EBs to iMKs provides a simple and efficient approach to generating clinically transfusible MKs and platelets.
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| Overall design |
We performed single cell RNA-Seq and assay for transposase-accessible chromatin sequencing to analyse the molecular mechanism of chemical reprogramming system.
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| Web link |
https://doi.org/10.1016/j.stem.2022.07.004
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| Contributor(s) |
Qin J, Zhang J, Jiang J, Li Y, Pei X |
| Citation(s) |
35931032 |
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| Submission date |
Jul 07, 2022 |
| Last update date |
Aug 30, 2022 |
| Contact name |
Jinhua Qin |
| E-mail(s) |
qinjinhuarhea@126.com
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| Organization name |
Beijing Institute of Transfusion
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| Street address |
Taiping Road
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| City |
Beijing |
| ZIP/Postal code |
100850 |
| Country |
China |
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| Platforms (1) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
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| Samples (12)
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| Relations |
| BioProject |
PRJNA856626 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE207654_RAW.tar |
2.4 Gb |
(http)(custom) |
TAR (of BW, MTX, TSV) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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