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Getting Physical (and Chemical) to Enhance Platelet Production

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Review of “Integrated Biophysical and Biochemical Signals Augment Megakaryopoiesis and Thrombopoiesis in a Three-Dimensional Rotary Culture System” from Stem Cells Translational Medicine by Stuart P. Atkinson

The production of platelets from stem cells could meet the need for the vast amounts of cells required for transfusion in patients suffering from hematological diseases or undergoing chemotherapy and/or radiotherapy. This would require the optimized clinical grade differentiation of large amounts of hematopoietic progenitor cells (HPCs) into megakaryocyte progenitor cells (megakaryopoiesis) and then the subsequent generation and release of platelets (thrombopoiesis) [1].

To do this, the laboratories of Erlie Jiang and Jiaxi Zhou (Chinese Academy of Medical Sciences and Peking Union Medical College) sought to combine multiple biochemical (small molecules) and biophysical signals through 3D cultivation in a rotary cell culture system (RCCS) [2, 3]. They hope that their new findings have the potential to generate the vast amount of cells required to treat patients in need [4].

Following a previously published protocol for platelet production under static conditions (SC) [1], the authors found a significant increase in megakaryopoiesis of CD34+ HPCs from cord blood, without an increase in HPC proliferation, when using the RCCS. Further cultivation in the RCCS also generated higher levels of pro-platelets as compared to SC and this was converted into a much higher yield of cells with ultrastructural and morphological characteristics similar to peripheral blood (PB) platelets. Furthermore, these RCCS-grown cells were as capable of shape change (lamellipodia extension), motility, and aggregation (See figure) as PB platelets, and better than those generated under SC.

So, as the RCCS enhances megakaryocytic differentiation and maturation, produces viable and functional intact platelets, is cost-effective and easy to manipulate, where do we go now? The application of these cells to the clinic is the obvious answer and, as a next step, the authors used their already implemented system to screen for small molecules which could further enhance large-scale in vitro platelet generation. This uncovered a positive contribution of Y-27632 (ROCK protein kinase inhibitor), 5-aza-2'-deoxycytidine (hypomethylating agent – known to boost platelet production), and RSPO2 (Wnt/b-catenin pathway activator), although the effects were more pronounced in the static conditions.

The authors suggest that shear force, simulated microgravity, better diffusion of nutrients and oxygen, and the application of the small molecules all enhanced platelet production, and they hope that these findings will propel in vitro produced platelets to where they are sorely needed – the clinic. Their strategy is cost-effective, easily manipulated, and feasible for the large-scale production of platelets, although further enhancements such as xeno-free conditions and FDA-approved compounds [5] will be required.

References

  1. Reems JA A journey to produce platelets in vitro. Transfusion 2011;51 Suppl 4:169S-176S.
  2. Li S, Ma Z, Niu Z, et al. NASA-approved rotary bioreactor enhances proliferation and osteogenesis of human periodontal ligament stem cells. Stem Cells Dev 2009;18:1273-1282.
  3. Wang Y, Zhang Y, Zhang S, et al. Rotating microgravity-bioreactor cultivation enhances the hepatic differentiation of mouse embryonic stem cells on biodegradable polymer scaffolds. Tissue Eng Part A 2012;18:2376-2385.
  4. Yang Y, Liu C, Lei X, et al. Integrated Biophysical and Biochemical Signals Augment Megakaryopoiesis and Thrombopoiesis in a Three-Dimensional Rotary Culture System. Stem Cells Transl Med 2016;5:175-185.
  5. Liu Y, Wang Y, Gao Y, et al. Efficient generation of megakaryocytes from human induced pluripotent stem cells using food and drug administration-approved pharmacological reagents. Stem Cells Transl Med 2015;4:309-319.