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Transcriptomic analysis of functional diversity of human umbilical cord blood hematopoietic stem/progenitor cells in erythroid differentiation

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Abstract

Hematopoietic stem cells (HSC) give rise to all types of blood lineages, including red blood cells (RBC). Hematopoietic stem/progenitor cells (HSPC) are known to be functionally diverse in terms of their self-renewal potential and lineage output. Consequently, investigation of molecular heterogeneity in the differentiation potential of HSPC is vital to identify novel regulators that affect generation of specific cell types, especially RBC. Here, we compared the erythroid potential of CD34+ hematopoietic stem and progenitor cells from 50 different umbilical cord blood (UCB) donors and discovered that those donors gave rise to diverse frequencies of Glycophorin-A+ erythroid cells after in vitro differentiation, despite having similar frequencies of phenotypic HSC initially. RNA sequencing revealed that genes involved in G protein-coupled receptor (GPCR) signaling were significantly up-regulated in the high-erythroid output donors. When we chemically modified two main signaling elements in this pathway, adenylyl cyclase (AC) and phosphodiesterase (PDE), we observed that inhibition of PDE led to 10 times higher yield of Glycophorin-A+ cells than activation of AC. Our findings suggest that GPCR signaling, and particularly the cAMP-related pathway, contributes to the diversity of erythroid potential among UCB donors.

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Acknowledgements

We thank Mark van der Garde for technical supports. This work was supported by the Swedish Research Council (No. 2018-02738) (K.M.), the Swedish Cancer Society (No. 19 0243 Pj) (K.M.). K.M. was funded by StemTherapy program at Lund University. The Lund Stem Cell Center was supported by a Center of Excellence grant in life sciences from the Swedish Foundation for Strategic Research.

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Authors and Affiliations

  1. Division of Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund University, Lund, Sweden

    Svetlana Soboleva & Kenichi Miharada

  2. Division of Molecular Hematology, Lund Stem Cell Center, Lund University, Lund, Sweden

    Hugo Åkerstrand

  3. International Research Center for Medical Sciences, Kumamoto University, Kumamoto, Japan

    Kenichi Miharada

Authors
  1. Svetlana Soboleva
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  2. Hugo Åkerstrand
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  3. Kenichi Miharada
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Contributions

KM designed the project. SS and KM planned experiments. SS performed experiments. SS, HÅ and KM analyzed the data. SS and KM wrote the manuscript.

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Correspondence to Kenichi Miharada.

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The authors declare that they have no conflict of interest.

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Soboleva, S., Åkerstrand, H. & Miharada, K. Transcriptomic analysis of functional diversity of human umbilical cord blood hematopoietic stem/progenitor cells in erythroid differentiation. Int J Hematol 115, 481–488 (2022). https://doi.org/10.1007/s12185-022-03292-1

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  • DOI: https://doi.org/10.1007/s12185-022-03292-1

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