Direct in vivo application of induced pluripotent stem cells is feasible and can be safe

Abstract

Increasing evidence suggests the consensus that direct in vivo application of induced pluripotent stem cells (iPSCs) is infeasible may not be true.Methods: Teratoma formation and fate were examined in 53 normal and disease conditions involving brain, lung, liver, kidney, islet, skin, hind limb, and arteries.Results: Using classic teratoma generation assays, which require iPSCs to be congregated and confined, all mouse, human, and individualized autologous monkey iPSCs tested formed teratoma, while iPSC-derived cells did not. Intravenously or topically-disseminated iPSCs did not form teratomas with doses up to 2.5×108 iPSCs/kg and observation times up to 18 months, regardless of host tissue type; autologous, syngeneic, or immune-deficient host animals; presence or absence of disease; disease type; iPSC induction method; commercial or self-induced iPSCs; mouse, human, or monkey iPSCs; frequency of delivery; and sex. Matrigel-confined, but not PBS-suspended, syngeneic iPSCs delivered into the peritoneal cavity or renal capsule formed teratomas. Intravenously administered iPSCs were therapeutic with a dose as low as 5×106/kg and some iPSCs differentiated into somatic cells in injured organs. Disseminated iPSCs trafficked into injured tissue and survived significantly longer in injured than uninjured organs. In disease-free animals, no intravenously administered cell differentiated into an unwanted long-lasting cell or survived as a quiescent stem cell. In coculture, the stem cell medium and dominant cell-type status were critical for iPSCs to form cell masses.Conclusion: Teratoma can be easily and completely avoided by disseminating the cells. Direct in vivo iPSC application is feasible and can be safe.

Clinical-Grade Human Pluripotent Stem Cells for Cell Therapy: Characterization Strategy

“…Single nucleotide polymorphism (SNP) arrays are based on probe binding and can detect changes in a genome with higher resolution (kb) than G-banding (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20). This method enables us to study copy number variations (CNVs), >20% mosaicism and loss of heterozygosity (LOH) but on the other hand, it is unable to detect <20% mosaicism, balanced chromosomal translocations, and inversions [30].…”

“…While some discuss the use of undifferentiated hiPSCs as a therapy product [18,19], the majority of hPSCs applications assume their directed differentiation before use, since undifferentiated cells can pose a risk of tumorigenicity. Many different cell types have been generated from hPSCs and some have already been used in clinical trials.…”

Diminished expression of major histocompatibility complex facilitates the use of human induced pluripotent stem cells in monkey

“…Human iPSCs were generated, cultured, and characterized as we previously described [20]. Briefly, peripheral blood nucleated cells were isolated and infected with Sendai viruses carrying a polycistronic construct of human Klf4, Oct3/4, Sox2, and c-Myc.…”

“…Cells were cultured on dishes coated with Matrigel diluted at 60: 1 (BD Biosciences) in mTeSR1 medium (STEMCELL Technologies, Canada). iPSC clones were amplified and then characterized by assessing the expression of pluripotency markers and through in vitro differentiation, alkaline phosphatase activity, and teratoma formation assays, in addition to karyotyping [20].…”

Modeling Parkinson’s Disease Using Induced Pluripotent Stem Cells

“…These cell-sorting technologies maintain the quality of transplanted cells and improve the safety and effectiveness of cell replacement therapy. Multiple animal trials have shown that iPSC transplantation is successful and safe in treating neurological diseases [146][147][148], and human clinical trials of Parkinson's disease using iPSCs are ongoing and observed [149][150][151]. Therefore, the iPSC treatment is expected to become a promising method for PD patients.…”