Engineering stem cell niches in bioreactors

Table 1 Examples of regulatory factors in bioreactors and their effects on stem cell engineering

Factors	Effects on stem cell niches	Ref.
Oxygen tension	Hypoxia promotes the proliferation of NSC, HSC, and MSC, inhibits spontaneous differentiation of humn PSC, and promotes iPSC reprogramming and growth	[21-24,33]
	Hypoxia promotes lineage specific differentiation from NSC, MSC and human PSC	[27,29,32]
Scaffold/ substrate cues	Higher cell proliferation rates under higher mechanical stresses; Substrate stiffness directs stem cell differentiation; Control of cell shape via substrate size directs human MSC differentiation	[38,41,44]
	3-D fibrous matrix promoted neural differentiation of ESC, silk scaffold promoted bone tissue formation from MSCs, honeycombs for cardiac tissue formation	[42,43,47,50]
	Enhanced MSC proliferation in collagen scaffolds in a radial-flow bioreactor	[51]
Decellularized ECMs	Decellularized bone matrix in a perfusion bioreactor promoted human PSC differentiation into bone tissue; Decellularized cardiac matrix promoted human PSC differentiation into cardiac lineage.	[55,58,59]
	Human PSC-derived ECM supported PSC proliferation	[56]
Mechanical forces	Mechanical stimulation significantly improved the function of engineered ligaments	[64]
	Mechanical compression enhanced MSC differentiation	[66]
	Dynamic compression with deformational loading and hydrostatic pressure improved cartilage tissue engineering;	[61]
	Hydrodynamic shear, cyclic flexure, and cyclic stretch accelerated heart valve tissue formation	[68]
	Pulsatile flow and circumferential stretch improved the engineered blood vessels	[119]
Electrical stimulation	Induced cellular tension and promoted cellular and functional properties of engineered cardiac tissue	[71,72]
	Electrical stimulation enhanced neural differentiation	[69,70]
Flow shear force	Lower flow (shear) rates enhanced MSC proliferation and higher flow (shear) rate increased osteogenic differentiation; Parallel flow and transverse flow affected osteogenic differentiation of human MSCs	[80,81]
	Perfusion improved tissue architecture of engineered cardiac muscle and increased matrix synthesis in engineered chondrocytes	[73,74]
	Agitation preserved Oct-4 expressing cells during PSC differentiation	[82,83]

NSC: Neural stem cells; HSC: Hematopoietic stem cells ESCs: Embryonic stem cells; MSCs: Mesenchymal stem cells; PSC: Pluripotent stem cells; iPSC: Induced pluripotent stem cells; ECM: Extracellular matrix.

Table 2 Microfluidics devices and microbioreactors in engineering stem cell niches

Microfluidic devices and microbioreactors	Stem cell type	Applications	Ref.
Gradient-generating microfluidic device	NSC	Proliferation and astrocyte differentiation	[91]
MEMS automated microfluidic device	AFSC	Adipogenic and osteogenic differentiation	[92]
3-D hydrogel incorporated microfluidics	NSC	3-D differentiation into neuronal and oligodendrocyte differentiation	[93]
Micro-grooved PDMS sheets with cyclic strain	MSC	MSC proliferation and differentiation	[94]
Microfluidic device with logarithmical flow rate	Mouse ESC	ESC adhesion and proliferation	[95]
A microfluidic chip which creates arbitrary culture media formulations	MSC	Proliferation, osteogenic	[96]
		differentiation and motility
A microscaffold cell chip with precisely controlled microenvironment	Retinal stem cells	Decrease apoptosis during the retinal differentiation	[98,99]
Microbioreactor array for 2-D and 3-D hydrogel cultures	Human ESC	Adjust flow rate and evaluate vascular differentiation	[100]
Microbioreactor arrays for drug screening	ESC, MSC	Incorporate 3D culture, biomaterials, etc. to screen drugs in a high-throughput manner	[103]
Compartmentalizing microfluidic devices	Cancer stem cells	Understanding of cell migration and cancer invasion	[104]
Microbioreactor array with 3-D fibrous matrix	Mouse ESC	High-through cell-based assay for drug screening	[14,87,102,106]
Microbioreactor array with full factorial design of growth factor combinations	Human ESC	Screening exogenous and paracrine factors in human ESC differentiation into mesoderm cells	[15]
Microfluidics with patterning and temporal analysis	PSC	Reveal paracrine/autocrine signaling for PSC self-renewal	[110]
Microbioreactor array with 3-D cell culture setting	EBs derived from human ESC or iPSC	PSC mesoderm differentiation, with controlled cytokine gradients.	[101]
Microfluidics with varying flow rates	PSC	Reveal paracrine/autocrine signaling during PSC self-renewal	[108,115]

NSC: Neural stem cells; AFSC: Amniotic fluid stem cells; ESCs: Embryonic stem cells; MSCs: Mesenchymal stem cells; PSC: Pluripotent stem cells; iPSC: Induced pluripotent stem cells; EBs: Embryoid bodies.