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.