# Whole Organ Engineering: Approaches, Challenges, and Future Directions
## 6 Supporting Technological Advances
### Stem Cell Technologies  
Human pluripotent stem cells, whether created via derivation from an embryo or through induced pluripotency, are capable of indefinite self-renewal and possess the ability to differentiate into essentially all mature cell types, and as a result are highly attractive candidate cell sources for engineering tissue [171; 172]. Human embryonic stem cells (hESCs) are derived from the inner cell mass of an embryo and have the intrinsic potential to differentiate into any type of cell because hESCs are the progenitors of every cell in the human body. hESCs have been successfully differentiated in vitro to become neural, cardiac, and pancreatic islet cells, among many others [171]. In addition to their differentiation potential, hESCs are favorable for tissue engineering and particularly for whole organ engineering because they can be cultured and expanded while in an undifferentiated, pluripotent state for an indefinite period of time, and as such could be expanded to produce a quantity of cells on the scale needed to seed organ sized tissue scaffolds before being differentiated into the functional cells needed [173]. However, even though they can be expanded in culture while undifferentiated, hESCs being derived from human embryos means the source is not very abundant and produces additional ethical considerations. Also, since hESCs cannot be sourced autologously, any potential use involving implantation of hESCs would require genetic modification to avoid an immune response. iPSCs are another form of hPSCs that address some of the drawbacks of hESCs, as iPSCs are sourced autologously. When delivering certain transcription factors to human adult cells placed in hESC culture conditions, the adult cells revert to a pluripotent state [174]. iPSCs are valuable in whole organ engineering because they offer a patient-specific cell source that, depending on the cell type, can also be abundantly sourced [175]. A patient-specific alternative to human pluripotent stem cells for whole organ engineering is adult stem cells. These are partially differentiated stem cells, such as mesenchymal or hematopoietic stem cells, derived from mature tissues that can differentiate into multiple different cell types and can be used to reconstruct organs from patient biopsies. Human adipose-derived mesenchymal stem cells were used to reconstruct bladders on decellularized ECM scaffolds in rat models to regenerate smooth muscle and nerve [139], and they were also used in a biohybrid esophagus implanted in rats to generate smooth muscle in a polycaprolactone and polyurethane tubular scaffold [151]. Adipose-derived mesenchymal stem cells (ADMSC) provide a unique advantage because they are abundant in host tissues, they can be harvested non-invasively, and they can be easily proliferated in culture to therapeutically appropriate levels [176]. ADMSCs have also been shown in some studies to have an immunoregulatory effect on surrounding tissues, preventing immuno-rejection of tissue grafts upon implantation in the host tissue [177]. Most importantly, ADMSCs can be differentiated into a number of different cell lineages, including muscle, endothelial, bone, cartilage, fat, and even neural tissue efficiently and reproducibly [178; 179; 180]. This makes ADMSCs suitable for engineering whole organs comprising these cells, as ADMSCs can be easily sourced and proliferated into a population large enough to seed an organ-sized construct and are patient-specific. An important consideration in developing engineered organs that incorporate stem cells or stem cell-derived cells is the tumorigenicity of pluripotent stem cells [178; 181; 182; 183; 184]. Both hESCs and iPSCs have been observed to form tumors comprising tissue from all three germ layers, called teratomas.