There is considerable excitement that human

induced pluripotent stem cells (hiPSCs) can

serve as a potentially safe and embryo-free

source of patient-specific cells for regenerative

medicine. Since 2007, when hiPSC lines were

first generated by Yu et al[1] and Takahashi et

al[2], a variety of methods have been reported

for reprogramming somatic cells to

pluripotency[3-7]. The ability of hiPSCs to

differentiate into derivatives of all three

embryonic germ layers is well established, and

rapid progress is being made towards controlled

in vitro differentiation of hiPSCs into specific

cell types, precursors as well as differentiated

progenies representing various tissues, such as

heart [8], pancreas [9], liver [10], eye including

retinal pigment epithelium cells(RPE) [11-14],

neuronal [15,16], and endothelial and

hematopoietic lineages [17-20]. Although these

studies clearly suggest a similar differentiation

potential between hiPSCs and human embryonic

stem cells (hESC), it is unclear whether they can

be expanded into homogeneous cell populations

suitable for use in drug discovery and clinical

translation.

We have developed an efficient method to

reproducibly generate large numbers of

bipotential progenitors—known as

hemangioblasts 􀃭 from multiple hESC lines

using an in vitro differentiation system [21,22].

These blast cells (BCs) expressed gene

signatures characteristic of hemangioblasts, and

could be differentiated into multiple

hematopoietic lineages as well as into

endothelial cells that could repair ischemic

vasculature in vivo[21]. Using hESC-derived

hemangioblasts/BCs as intermediates, we have

also generated functional oxygen-carrying

erythrocytes on a large scale from multiple hESC

lines, demonstrating the robust expansion

capability of these cells[23]. This system

provides an excellent model for evaluation and

comparison of hiPSC derivatives to their hESC

counterparts. In the present study, we

successfully generated BCs, endothelial cells,

and hematopoietic cells from multiple wellcharacterized

hiPSC lines. We further compared

the functional characteristics of BCs derived

from hESCs and hiPSCs, and found that

hemangioblastic derivatives generated from

these hiPSC lines display abnormal molecular

and/or cellular processes compared to their

corresponding hESC counterparts. Similarly,

RPE cells derived from hiPSCs begin senescing

in the first passage, indicating the observed

phenomenon is not limited to hemangioblastic

lineages