Developmental Potential of the Murine Embryonic Stem Cells Transplanted into the Healthy Rat Brain - Novel Insights into Tumorigenesis

Abstract

Although engraftment of undifferentiated pluripotent embryonic stem cells (ESCs) into the injured central nervous system (CNS) may lead to targeted cell replacement of lost/damaged cells, sustained proliferative activity combined with uncontrolled differentiation of implanted cells presents a risk of tumor formation. As tumorigenic potential is thought to be associated with pluripotency of embryonic stem cells, pre-differentiation may circumvent this problem. Recently, it has been demonstrated that tumorigenesis occurs despite pre-differentiation if the neural precursor cells are implanted into the brain of a homologous animal (e.g., mouse to mouse). However, xenotransplantation (e.g., mouse to rat) without pre-differentiation, lead to the development of healthy neuronal cells, in absence of tumor formation, suggesting that tumor-suppressive effects of host tissue on engrafted ESCs may play a role in transplant tumorigenesis. We critically investigated tumorigenesis and possible mechanisms of anticipated tumor-suppressive effect under conditions analogous to previously published studies. Xenotransplantation of D-3 murine ESCs into uninjured adult rat brains lacking any preliminary inflammatory potential was found to lead to tumor formation in 5 out of 8 of animals within 2 weeks postimplantation. Tumor-suppressive effects, reflected by Erdo et. al could possibly be ascribed to immunomodulatory activity of macrophages scavenging the tumorigenic fraction of the implanted cells. The importance of number of engrafted cells, implantation site and immunosuppressive effects are discussed as possible variables determining tumorigenic outcome after ESC transplantation.

What Do We Know About the Detailed Mechanism on How Stem Cells Generate Their Mode of Action

“…Macrophage infiltration was shown to be less pronounced when stem cells were implanted into completely intact healthy brains. We therefore suggested that the massive macrophage infiltration at graft sites might be ascribed to the combined stimulus exhibited by the FP brain injury and the cell implantation (Molcanyi 2009). …”

“…As we believe, the tumorigenic fraction of implanted graft may have been scavenged by activaed macrophages, alongside with concomitant survival of stem cells turning into healthy neural phenotypes. Great caution is needed when stem cells are implanted in experimental settings of diseases associated with inflammatory response (such as stroke or traumatic brain injury) as the tumorigenic threat may stay unveiled (in case tumorigenic fraction is being removed by activated immune cells) (Molcanyi 2009). …”

Stem Cells: Epigenetic Basis of Differentiation

“…The open chromatin conformation seen at multiple promoter regions in ES cells also suggests the rationale for open chromatin structure in stem cells. Adults stem cells are also a potentially safer cell source, compared to embryonic stem cells, which are known to form teratomas, a specific type of tumour consisting of derivatives of all three germ layers when implanted into ectopic sites [49,50]. This effect has not been reported following implantation of adult stem (progenitor) cells.…”

Novel Regenerative Solutions Induce Rapid Adipogenic Differentiation of Mesenchymal Stem Cells with No Evidence of Transformation or Osteogenic Differentiation

“…However, compared to embryonic stem cells (ESCs), adult stem cells such as Other potential advantages of MSCs are a lower probability of tumor formation compared to ESCs, and their ability to be transplanted across allogeneic barriers (Trzaska et al (2009), Mohseny et al (2009), Molcanyi et al (2009) ). The latter provides MSCs with a major advantage since these cells could be immediately available as an offthe-shelf source.…”