Hemangioblastic Derivatives from Human Induced Pluripotent Stem Cells Exhibit Limited Expansion and Early Senescence

Abstract

Human induced pluripotent stem cells (hiPSC) have been shown to differentiate into a variety of replacement cell types. Detailed evaluation and comparison with their human embryonic stem cell (hESC) counterparts is critical for assessment of their therapeutic potential. Using established methods, we demonstrate here that hiPSCs are capable of generating hemangioblasts/blast cells (BCs), endothelial cells, and hematopoietic cells with phenotypic and morphologic characteristics similar to those derived from hESCs, but with a dramatic decreased efficiency. Furthermore, in distinct contrast with the hESC derivatives, functional differences were observed in BCs derived from hiPSCs, including significantly increased apoptosis, severely limited growth and expansion capability, and a substantially decreased hematopoietic colony-forming capability. After further differentiation into erythroid cells, >1,000-fold difference in expansion capability was observed in hiPSC-BCs versus hESC-BCs. Although endothelial cells derived from hiPSCs were capable of taking up acetylated low-density lipoprotein and forming capillary-vascular-like structures on Matrigel, these cells also demonstrated early cellular senescence (most of the endothelial cells senesced after one passage). Similarly, retinal pigmented epithelium cells derived from hiPSCs began senescing in the first passage. Before clinical application, it will be necessary to determine the cause and extent of such abnormalities and whether they also occur in hiPSCs generated using different reprogramming methods. STEM CELLS 2010;28:704-712 Disclosure of potential conflicts of interest is found at the end of this article.

Red blood cell generation from human induced pluripotent stem cells: perspectives for transfusion medicine

“…23 One group recently reported that hiPSC are capable of generating hemangioblast/blast cells, endothelial cells, hematopoietic cells and erythroblastic differentiation without terminal differentiation. 17 This group mainly showed functional differences between hESC and hiPSC including significantly increased apoptosis, severely limit- 17 we observed a difference between hiPSC and hESC lines regarding the amplification and percentage of enucleated RBC. The possibility of manufacturing cultured RBC concentrates would lead to many dramatic improvements in transfusion practice.…”

“…Although hematopoietic differentiation has been explored, [15][16][17] no terminal erythroid differentiation has been reported to date.…”

Reprogramming and Carcinogenesis—Parallels and Distinctions

“…It has been i.e. shown that human iPS-derived early blood progenitor cells appear to undergo premature senescence (Feng et al, 2010). It was also suggested that in order to control the efficiency of iPS generation, senescence may be activated by tumor suppressors like p53 and p16(INK4a) (Banito and Gil, 2010).…”

“…Increased propensity to form teratomas (Hanley et al, 2010;Miura et al, 2009) Forms tumors by definition (Galli et al, 2004;Ribatti, 2012) p53 p53 loss increases pluripotency (Hanna et al, 2009;Hong et al, 2009;Kawamura et al, 2009) p53 loss increases tumor initiation frequency (Godar et al, 2008; Senescence Premature senescence (Feng et al, 2010) Reduced senescence (Karimi-Busheri et al, 2010;Sabisz and Skladanowski, 2009) …”

Quelles cellules souches pour une réparation du pancréas endocrine ?

“…Malgré l'intérêt croissant de la communauté scientifique pour les cellules iPS, plusieurs problèmes devront être résolus avant de penser à leur utilisation clinique. Les iPS conservent en effet des traces de la mémoire épigé-nétique des cellules spécialisées dont elles proviennent [25], et subissent, dans certains cas, un vieillissement accéléré [26]. Enfin, une difficulté majeure est le risque d'induction de mutations et d'activation d'oncogènes lors du processus de reprogrammation, et ce quelle que soit la méthode employée [27].…”