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The Abca4/miR-351-3p – The Key to Therapeutic Success in Amniotic Fluid MSCs?

Review of “miR-351-3p promotes rat amniotic fluid-derived mesenchymal stromal cell proliferation via targeting the coding sequence of Abca4” from STEM CELLS by Stuart P. Atkinson

Studies analyzing amniotic fluid-derived mesenchymal stem cells (AFMSCs) isolated at different gestational ages have provided evidence for significant differences in proliferative and regenerative capacities [1, 2] and transcriptional profiles [2-5] (See the STEM CELLS article here!). To explore the root of these differences, researchers led by Zhengwei Yuan (China Medical University, Shenyang, Liaoning, China) compared rat AFMSCs isolated at four progressive gestational ages to understand the molecular mechanisms that support the observed stage-specific differences. In their recent STEM CELLS article, Huang et al. report that an Abca4/miR-351-3p axis may represent an exciting way to generate AFMSCs with a proliferative capacity suited to regenerative medicine applications [6].

The author’s analysis provided evidence that rat AFMSCs derived at earlier pregnancy stages displayed significant differences to those derived at later timepoints, with early pregnancy-stage AFMSCs displaying a significantly higher proliferative capacity. Subsequent integrated bioinformatics analyses of transcriptome data established the differential expression of Abca4 and suggested that Abca4 expression led to a reduction in AFMSC proliferation. ABCA4 belongs to the adenosine triphosphate-binding cassette transporter family and is a transmembrane transporter of vitamin A intermediates [7, 8]. The authors confirmed a link between Abca4 expression and reduced proliferation using Abca4 knockout and overexpression experiments. Finally, the authors employed dual-luciferase reporter assays to show that the miR-351-3p microRNA targets the coding sequence of Abca4 mRNA to reduce expression levels and increase AFMSC proliferation.

Overall, these data suggest that the lower proliferative capacity of late pregnancy-stage AFMSCs derives from the higher expression of Abca4 compared to early pregnancy-stage AFMSCs. Therefore, the authors suggest that modulating Abca4 expression, perhaps through miR-531-3p levels, may represent a means to improve the therapeutic capacity of in vitro cultured AFMSCs.

For more on how to improve the therapeutic potential of amniotic fluid-derived mesenchymal stem cells, stay tuned to the Stem Cells Portal!


References

  1. Schiavo AA, Franzin C, Albiero M, et al., Endothelial properties of third-trimester amniotic fluid stem cells cultured in hypoxia. Stem Cell Research & Therapy 2015;6:209.
  2. Moschidou D, Mukherjee S, Blundell MP, et al., Valproic Acid Confers Functional Pluripotency to Human Amniotic Fluid Stem Cells in a Transgene-free Approach. Molecular Therapy 2012;20:1953-1967.
  3. Moraghebi R, Kirkeby A, Chaves P, et al., Term amniotic fluid: an unexploited reserve of mesenchymal stromal cells for reprogramming and potential cell therapy applications. Stem Cell Research & Therapy 2017;8:190.
  4. Spitzhorn L-S, Rahman MS, Schwindt L, et al., Isolation and Molecular Characterization of Amniotic Fluid-Derived Mesenchymal Stem Cells Obtained from Caesarean Sections. Stem Cells International 2017;2017:5932706.
  5. Tsai M-S, Hwang S-M, Chen K-D, et al., Functional Network Analysis of the Transcriptomes of Mesenchymal Stem Cells Derived from Amniotic Fluid, Amniotic Membrane, Cord Blood, and Bone Marrow. STEM CELLS 2007;25:2511-2523.
  6. Huang J, Zhao Q, Wei X, et al., miR-351-3p promotes rat amniotic fluid-derived mesenchymal stromal cell proliferation via targeting the coding sequence of Abca4. STEM CELLS 2021;39:1192-1206.
  7. Holland IB, ABC transporters, mechanisms and biology: an overview. Essays in Biochemistry 2011;50:1-17.
  8. Koenekoop RK, The gene for Stargardt disease, ABCA4, is a major retinal gene: a mini-review. Ophthalmic Genetics 2003;24:75-80.