Growing Vascularized Heart Tissue From Stem Cells

Abstract

The promise of stem cells to repair the heart after damage or heart attack has not been realized because most such cells are lost after transplantation. A new approach is to grow substantial viable pieces of cardiac tissue from human stem cells by cardiac tissue engineering. Such constructs must be fully vascularized and perfused to ensure the viability of clinically relevant volumes of tissue. This requires careful choice of cells, culture conditions, a biomaterial to act as scaffold, and crucial strategies for vascularization. Autologous stem cells with high plasticity, which would avoid the need for antirejection therapies after transplantation, are an attractive source of both cardiomyocytes and vascular cells. Most stem cells also have inherent paracrine activity, releasing cytoprotective factors and growth-promoting cytokines that can further stimulate tissue regeneration and neovascularization through recruitment of endogenous stem and progenitor cells. Current advances for growing vascularized and functional cardiac constructs with human stem cells are described, bringing us a step closer to the engineering of complex cardiac tissues such as pacemaker, conducting tissue, or contractile myocardial flaps ideal for transplantation. From studies in rats successful transplantation of thin constructs to the ventricle has been reported, but there remain further issues to resolve before larger human constructs will be available to test in the clinic.

Biomaterials for Cardiac Regeneration

“…Donor cells should be high proliferative or selfrenewable to allow ex vivo large-scale expansion needed for human-scale in vitro engineering, they should have the capacity to differentiate into relevant functional cardiac cells (particularly into contractile force generating cardiomyocytes), they should exert benefi cial paracrine activity to ensure proper in vitro and in vivo cell maturation and viability, and they should be allogeneic or of low immunogenic profi le to obviate requirement for long-term immunosuppressant therapy (Lim et al 2013 ). Since, in case of the heart, it is not possible-yet-to isolate differentiated cardiac cells and expand them into the amounts needed for human-scale in vitro engineering (Soonpaa and Field 1998 ), the most promising candidates still seem to be stem or progenitor cells.…”

“…In the past there has already been quite some experience using stem and progenitor cells for clinical relevant cardiovascular regenerative medicine approaches (Lim et al 2013 ), with the cells in use broadly categorized as embryonic stem cells (ESCs), fetal cells (FSCs), adult-derived stem or progenitor cells, and adult-derived inducible pluripotent stem cells (iPSCs)-all of them having their assets and drawbacks.…”

“…Reendothelialization strategies and the most suitable cell type are still a question of intensive debate in the tissue-engineering community. Cell populations for in vitro and in vivo models of angiogenesis and vasculogenesis vary from human dermal microvascular ECs (HDMECs) to human umbilical vein ECs (HUVECs) and endothelial progenitor cells (EPCs) among others, with additional coculture modalities involving non-endothelial cells that may further support and partially enhance angiogenic mechanisms (Lokmic and Mitchell 2008, Lim et al 2013, Krawiec and Vorp 2012, Nesselmann et al 2010. Further work is needed in order to integrate donor endothelial cells in into a long-term functional vascular system (Aubin et al 2013b ).…”

Combined Usage of Stem Cells in End‐Stage Heart Failure Therapies

“…Advances in regenerative tissue engineering using autologous stem or progenitor cells hold great potential to create a bioartifical heart [Taylor, ]. Recent developments have successfully decellularized a murine heart and recellularized the cardiac scaffolding with pluripotent stem cells to give rise to a beating murine heart [Ott et al, ; Taylor, ; Badylak et al, ; Lim et al, ]. It is tantalizing to consider a day when stem cells are used to create a personalized organ, thereby addressing issues from donor organ shortages, immunosuppression side effects, and TV.…”

“…Progression of TV occurs due to a mismatch between two biologic processes: endogenous vascular repair, likely driven by EPCs, and progressive innate and adaptive immune‐mediated vascular injury. Endothelial regenerative strategies using genetic manipulation of EPCs has been performed in animal models, resulting in accelerated endothelial regeneration, increased incorporation of EPCs into vascular endothelium and attenuation of TV [Feng et al, , ; Lim et al, ]. Hematopoietic chimerism is another attractive therapeutic option to induce allograft tolerance and therefore eliminate or minimize TV related to chronic rejection.…”