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Towards the Three-dimensional Bioprinting of a Human Heart

Review of “In Situ Expansion, Differentiation, and Electromechanical Coupling of Human Cardiac Muscle in a 3D Bioprinted, Chambered Organoid” from Circulation Research by Stuart P. Atkinson

The inability of cardiomyocytes to proliferate or migrate represents a challenge in reaching the high-cell densities required to generate human cardiac muscle through three-dimensional bioprinting [1]. As an alternative strategy, researchers led by Brenda M. Ogle (University of Minnesota, Minneapolis, MN, USA) hypothesized that they could first print highly-proliferative human induced pluripotent stem cells (iPSCs) and then induce cardiomyocytic differentiation following the attainment of the desired cell density. 

In their new study, the Ogle team took advantage of their previously reported cardiomyocyte differentiation-inducing extracellular matrix formulation [2] to create a bioink that supports iPSC proliferation [3]. Fascinatingly, they now report on the application of their iPSC- and extracellular matrix bioink-based approach to develop a chambered muscle pump that may pave the way to the generation of complex heart-like structures.

Kupfer et al. optimized a photo-cross-linkable gelatin methacrylate-based formulation of native extracellular matrix proteins (fibronectin, laminin-111, and collagen) with the potential to support iPSC proliferation and cardiomyocytic differentiation. The team then used this as the base of a bioink to three-dimensionally print human iPSC-laden structures composed of two chambers and a vessel inlet and outlet via the implementation of free-form reversible embedding of suspended hydrogels. 

After proliferating human iPSCs reach the required density, the authors prompted in-structure differentiation into cardiomyocytes using a small molecule-based differentiation protocol to yield a chamber possessing muscle walls of up to 500 μm in thickness. At the functional level, the resultant human chambered muscle pump demonstrated macroscale beating and continuous action potential propagation with responsiveness to drugs and pacing up to six weeks after fabrication. Furthermore, the connected chambers allowed for perfusion and enabled the replication of the pressure/volume relationships fundamental to the study of heart function and remodeling with health and disease.

The authors hope that their findings will pave the way for the application of human chambered muscle pumps of this type in cardiology assays, injury and disease modeling, medical device testing, and regenerative medicine research, although the approach described could be applied to other cell types with low proliferative and migratory capacity following differentiation into other tissues. The further improvements required to take the research to this level include the need to increase the thickness, homogeneity, and organization of the muscle wall and spur the maturation of individual cardiac muscle cells.

For more on the advanced bioprinting of human tissues and organs, stay tuned to the Stem Cells Portal!

References

  1. Lee A, Hudson AR, Shiwarski DJ, et al., 3D bioprinting of collagen to rebuild components of the human heart. Science 2019;365:482.
  2. Jung JP, Hu D, Domian IJ, et al., An integrated statistical model for enhanced murine cardiomyocyte differentiation via optimized engagement of 3D extracellular matrices. Scientific Reports 2015;5:18705.
  3. Kupfer Molly E, Lin W-H, Ravikumar V, et al., In Situ Expansion, Differentiation, and Electromechanical Coupling of Human Cardiac Muscle in a 3D Bioprinted, Chambered Organoid. Circulation Research 2020;127:207-224.