Regenerative medicine offers a curative approach to treating heart disease through multiple emerging therapeutic concepts. Decellularized organ scaffolds are being optimized to guide and spatially organize stem cell differentiation in efforts to rebuild functional tissues. Additionally, pluripotent stem cells offer a transformative cell source to differentiate into the full spectrum of cellular building blocks. Adult cardiac tissues have been used as extracellular scaffolds as a proof of principle; however, matching the developmental stages of embryonic scaffold with primitive cardiac progenitors may be used to optimize the differentiation and maturation of bioengineered cardiac tissues. Our novel approach uses embryo-derived decellularized hearts as scaffolds to promote embryonic stem cell differentiation. Further, we determined that agitation with 0.25% sodium dodecyl sulfate (SDS) solution was the most effective protocol to maintain matrix integrity while eliminating endogenous cells. The scaffolds were successfully reseeded with different cellular sources derived from pluripotent stem cells to achieve beating cardiac tissues characterized by endothelial, cardiac, and smooth muscle markers. Therefore, embedding stem cells within a tissue-specific environment matched to the developmental stage of the progenitors may offer a practical solution for stem-cell-derived applications such as disease modeling, pharmaceutical safety testing, and screening of novel therapeutic targets. 1. Introduction Regenerative medicine offers a new paradigm for the treatment of heart disease through replacement of damaged cardiac tissue with adult, embryonic, or induced pluripotent stem cells (iPSC). Due to a limited capacity of the heart to innately regenerate, multiple strategies are being explored and tested to optimize stem cell-based regeneration [1]. The niche environment in which stem cells reside has been identified as a critical component to the effectiveness of cellular engraftment and differentiation [2]. Therefore, delivering cardiac competent progenitors into a nurturing environment remains the focus of ongoing discovery pipelines. To enable this outcome, pluripotent stem cell sources including embryonic stem cells (ESC) or their bioengineered counterparts, iPSCs, offer a significant advantage for cardiac regeneration due to their high proliferative as well as tissue-specific differentiation capacity. However, their pluripotent state carries the major risk of uncontrolled growth resulting in teratoma formation or disorganized nonfunctional tissues [3, 4]. In
References
[1]
B. C. du Pre, P. A. Doevendans, and L. W. van Laake, “Stem cells for cardiac repair an introduction,” Journal of Geriatric Cardiology, vol. 10, pp. 186–197, 2013.
[2]
A. Alcon, E. Cagavi Bozkulak, and Y. Qyang, “Regenerating functional heart tissue for myocardial repair,” Cellular and Molecular Life Sciences, pp. 1–22, 2012.
[3]
J. Leor, S. Gerecht, S. Cohen et al., “Human embryonic stem cell transplantation to repair the infarcted myocardium,” Heart, vol. 93, no. 10, pp. 1278–1284, 2007.
[4]
T. A. Prokhorova, L. M. Harkness, U. Frandsen et al., “Teratoma formation by human embryonic stem cells is site dependent and enhanced by the presence of Matrigel,” Stem Cells and Development, vol. 18, no. 1, pp. 47–54, 2009.
[5]
A. Smith, N. G. Nelson, S. Oommen, et al., “Apoptotic susceptibility to DNA damage of pluripotent stem cells facilitates pharmacologic purging of teratoma risk,” Stem Cells Translational Medicine, vol. 1, pp. 709–718, 2012.
[6]
V. F. M. Segers and R. T. Lee, “Biomaterials to enhance stem cell function in the heart,” Circulation Research, vol. 109, no. 8, pp. 910–922, 2011.
[7]
J. Cortiella, J. Niles, A. Cantu et al., “Influence of acellular natural lung matrix on murine embryonic stem cell differentiation and tissue formation,” Tissue Engineering A, vol. 16, no. 8, pp. 2565–2580, 2010.
[8]
P. M. Crapo, T. W. Gilbert, and S. F. Badylak, “An overview of tissue and whole organ decellularization processes,” Biomaterials, vol. 32, no. 12, pp. 3233–3243, 2011.
[9]
S. L. J. Ng, K. Narayanan, S. Gao, and A. C. A. Wan, “Lineage restricted progenitors for the repopulation of decellularized heart,” Biomaterials, vol. 32, no. 30, pp. 7571–7580, 2011.
[10]
M. Prideaux, N. Loveridge, A. A. Pitsillides, and C. Farquharson, “Extracellular matrix mineralization promotes E11/gp38 glycoprotein expression and drives osteocytic differentiation,” PLoS ONE, vol. 7, no. 5, Article ID e36786, 2012.
[11]
S. K. Goh, S. Bertera, P. Olsen, et al., “Perfusion-decellularized pancreas as a natural 3D scaffold for pancreatic tissue and whole organ engineering,” Biomaterials, vol. 34, pp. 6760–6772, 2013.
[12]
H. C. Ott, B. Clippinger, C. Conrad et al., “Regeneration and orthotopic transplantation of a bioartificial lung,” Nature Medicine, vol. 16, no. 8, pp. 927–933, 2010.
[13]
H. C. Ott, T. S. Matthiesen, S.-K. Goh et al., “Perfusion-decellularized matrix: using nature's platform to engineer a bioartificial heart,” Nature Medicine, vol. 14, no. 2, pp. 213–221, 2008.
[14]
E. A. Ross, M. J. Williams, T. Hamazaki et al., “Embryonic stem cells proliferate and differentiate when seeded into kidney scaffolds,” Journal of the American Society of Nephrology, vol. 20, no. 11, pp. 2338–2347, 2009.
[15]
B. E. Uygun, A. Soto-Gutierrez, H. Yagi et al., “Organ reengineering through development of a transplantable recellularized liver graft using decellularized liver matrix,” Nature Medicine, vol. 16, no. 7, pp. 814–820, 2010.
[16]
T. Eschenhagen and W. H. Zimmermann, “Engineering myocardial tissue,” Circulation Research, vol. 97, no. 12, pp. 1220–1231, 2005.
[17]
J. M. Wainwright, C. A. Czajka, U. B. Patel et al., “Preparation of cardiac extracellular matrix from an intact porcine heart,” Tissue Engineering C, vol. 16, no. 3, pp. 525–532, 2010.
[18]
J. Liao, J. Erinn, and M. Sacks, “Effects of decellularization on the mechanical and structural properties of the porcine aortic valve leaflet,” Biomaterials, vol. 29, pp. 1065–1074, 2008.
[19]
A. Martinez-Fernandez, T. J. Nelson, S. Yamada et al., “iPS programmed without c-myc yield proficient cardiogenesis for functional heart chimerism,” Circulation Research, vol. 105, pp. 648–656, 2009.
