stromal

cells,

which

were

able

to

myeloid

colony-forming

[1]. Moreover, Coculture of hPSCs with OP9 bone marrow stro-

mal cells or with mAGM-S3 can also generation of multilineage

HSPCs [3, 5, 6]. The differentiation efficiency of embryoid bodies

(EBs)-based model is low due to the heterogeneity of cell types and

the lack of access to nutrients of internal cells [7]. Additionally,

coculture with mouse feeder cells leads to human cells coming into

contact with cells of foreign species, which may be detrimental to

subsequent therapeutic applications.

Hematopoietic differentiation from hPSCs in chemically

defined systems were also developed [6, 8], but often involves

culturing in specialized medium and many steps of the differentia-

tion, which make the cost of HPSCs very expensive and it is difficult

to produce the large-scale of HPSCs. To promote hematopoietic

differentiation of hPSCs, the proper use of growth factors and

cytokines to benefit the production of HSPCs were investigated.

Kennedy et al. reported that inhibition of Nodal/Activin pathway

during hematopoiesis from human ESCs in a chemically defined

medium containing the SB-431542, can induce the development

of definitive HSPCs and blocked the primitive hematopoiesis pro-

cess [9]. The canonical Wnt pathway is also known to play a vital

role in the induction of definitive HPSCs derived from human

ESCs [10]. Treatment of human ESCs with GSK-3 inhibitor

CHIR99021 by activation of canonical Wnt signaling can promote

definitive hematopoiesis and inhibited the number of primitive

HSPCs

[11].

In

contrast,

treating

human

ESCs

with the

Wnt-antagonist

IWP2

augmented

the

number

of

primitive

HSPCs. In keeping with this study, Wang et al. reported that

R-spondin2 plays a key role in early hematopoietic differentiation

of hPSCs that increased the generation of APLNR⁺ mesoderm cells

by activating TGF beta signaling [12]. In another approach, ectopic

expression of transcription factors promotes the hematopoietic

commitment of hPSCs by increasing the expression of mesoderm,

hemogenic endothelial and the genes associated with hematopoie-

tic development. Ran et al. demonstrated that expression of endog-

enous RUNX1a promotes hematopoietic lineage commitment

from hPSCs and enhanced definitive hematopoiesis [13]. It has

also been shown that ectopic expression of HOXA9 increased

hematopoietic

commitment

from

human

ESCs;

however,

HOXA9 was not sufficient to confer in vivo long-term engraftment

potential [14]. Interesting, a recent study reported that suppression

of MSX2 enhances hematopoietic differentiation of hPSCs via inhi-

bition of TGF beta signaling [15].

Recent work has indicated the importance of the local physical

environment (such as blood flow, wall shear stress) in regulating

HE specification and HSPC production [16–18]. To mimic the

physical microenvironment, some bioengineering techniques that

promote

hematopoiesis

from

hPSCs

have

been

applied

[19, 20]. Additionally, the combination of bioreactors and

56

Xiaohua Lei et al.