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Review Articles: Engineering Cell Microenvironment Using Novel Hydrogels

Engineering Embryonic Stem Cell Microenvironments for Tailored Cellular Differentiation

[+] Author and Article Information
Chenyu Huang

Department of Plastic, Reconstructive and
Aesthetic Surgery,
Beijing Tsinghua Changgung Hospital,
Medical Center,
Tsinghua University,
Beijing 100084, China;
Department of Plastic Surgery,
Meitan General Hospital,
Beijing 100028, China
e-mail: huangchenyu2014@126.com

Alexander Melerzanov

Cellular and Molecular Technologies Laboratory,
MIPT,
Dolgoprudny 141701, Russia

Yanan Du

Department of Biomedical Engineering,
School of Medicine,
Collaborative Innovation Center for Diagnosis
and Treatment of Infectious Diseases,
Tsinghua University,
Beijing 100084, China
e-mail: duyanan@tsinghua.edu.cn

1Corresponding authors.

Manuscript received October 8, 2015; final manuscript received March 9, 2016; published online May 6, 2016. Assoc. Editor: Feng Xu.

J. Nanotechnol. Eng. Med 6(4), 040801 (May 06, 2016) (10 pages) Paper No: NANO-15-1086; doi: 10.1115/1.4033193 History: Received October 08, 2015; Revised March 09, 2016

The rapid progress of embryonic stem cell (ESCs) research offers great promise for drug discovery, tissue engineering, and regenerative medicine. However, a major limitation in translation of ESCs technology to pharmaceutical and clinical applications is how to induce their differentiation into tailored lineage commitment with satisfactory efficiency. Many studies indicate that this lineage commitment is precisely controlled by the ESC microenvironment in vivo. Engineering and biomaterial-based approaches to recreate a biomimetic cellular microenvironment provide valuable strategies for directing ESCs differentiation to specific lineages in vitro. In this review, we summarize and examine the recent advances in application of engineering and biomaterial-based approaches to control ESC differentiation. We focus on physical strategies (e.g., geometrical constraint, mechanical stimulation, extracellular matrix (ECM) stiffness, and topography) and biochemical approaches (e.g., genetic engineering, soluble bioactive factors, coculture, and synthetic small molecules), and highlight the three-dimensional (3D) hydrogel-based microenvironment for directed ESC differentiation. Finally, future perspectives in ESCs engineering are provided for the subsequent advancement of this promising research direction.

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Fig. 1

A schematic illustration of engineering approaches for tailored ESC differentiation. Top: modulation of ESC niche on 2D substrates by diverse biophysical and biochemical cues. Bottom: ESC niche modulation within 3D hydrogel, synthetic scaffolds, and decellularized scaffolds. (Reproduced with permission from Xu et al. [9]. Copyright 2013 by Springer Science+Business Media).

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Fig. 2

Biophysical regulation of ESC fate on 2D substrate. (a) Geometrical constraint: microcontact printing (top), resulting in hESCs colonies with upregulation of endoderm marker as colonies size decreased (bottom) [5,7]; (b) cyclic strain as mechanical stimulation (top) and vascular differentiation of mESC (bottom) [15,16]; (c) matrix stiffness of the polymeric substrate: cell morphology regulated by substrate stiffness (top) and preferable osteogenic differentiation of mESCs on stiffer substrate [17,18]; (d) nanoscale structures fabricated by electrospun nanofibers (left), which was used to induce hESC neuronal differentiation (right) [19,20]. (Reproduced with permission from Xu et al. [9]. Copyright 2013 by Springer Science+Business Media).

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Fig. 3

Biochemical strategies for ESC regulation on 2D substrate. (a) Protocol (top) and dynamic morphogenesis (bottom) during ESC-derived hepatic differentiation [46]. SOX17, HEX, and HNF4α transfected ESCs; (b) left: suppression of Wnt/β-catenin signaling pathway with soluble and substrate-immobilized IGFBP4 [47]. Right: improved cardiac differentiation of ESC according to MF20 (anti-α myosin heavy chain) staining; (c) left: micropatterned coculture of mESC and stellate cells for induction to hepatic lineage [48]. Right: stronger intracellular alpha fetoprotein (hepatocyte marker) of mESC expression in cocultures as compared to monoculture, suggesting improved differentiation efficiency. (Reproduced with permission from Xu et al. [9]. Copyright 2013 by Springer Science+Business Media).

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Fig. 4

ESC differentiation regulated by 3D culture configuration. (a) Images (left) and live/dead staining (right) of hESCs cultured in 3D alginate microcapsules [63]. (Middle) Suppression of NANOG (pluripotent marker) and upregulation of SOX17 and FOXA2 (hepatocyte markers) on day 10; (b) left: scanning electronic microscopy images (pseudocolored) of hESCs within electrospun PU nanofibers (5000X magnification) [40]. Middle: distribution of pore diameter of PU scaffolds peaks at 5–6 and 1 μm. Right: hESC-derived neurons after 47 days cultured indicated by upregulated MAP2ab (mature neural marker); (c) Left: decellularization and reseeding for cardiac tissue engineering [64]. Right: immunostaining detection of CD31 (endothelial marker, green) on the reseeded decellularized heart sections with hESC-derived cells. (Reproduced with permission from Xu et al. [9]. Copyright 2013 by Springer Science+Business Media).

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