Bioreactors to influence stem cell fate: Augmentation of mesenchymal stem cell signaling pathways via dynamic culture systems

Abstract

Background Mesenchymal stem cells (MSCs) are a promising cell source for bone and cartilage tissue engineering as they can be easily isolated from the body and differentiated into osteoblasts and chondrocytes. A cell based tissue engineering strategy using MSCs often involves the culture of these cells on three-dimensional scaffolds; however the size of these scaffolds and the cell population they can support can be restricted in traditional static culture. Thus dynamic culture in bioreactor systems provides a promising means to culture and differentiate MSCs in vitro. Scope of Review This review seeks to characterize key MSC differentiation signaling pathways and provides evidence as to how dynamic culture is augmenting these pathways. Following an overview of dynamic culture systems, discussion will be provided on how these systems can effectively modify and maintain important culture parameters including oxygen content and shear stress. Literature is reviewed for both a highlight of key signaling pathways and evidence for regulation of these signaling pathways via dynamic culture systems. Major Conclusions The ability to understand how these culture systems are affecting MSC signaling pathways could lead to a shear or oxygen regime to direct stem cell differentiation. In this way the efficacy of in vitro culture and differentiation of MSCs on three-dimensional scaffolds could be greatly increased. General Significance Bioreactor systems have the ability to control many key differentiation stimuli including mechanical stress and oxygen content. The further integration of cell signaling investigations within dynamic culture systems will lead to a quicker realization of the promise of tissue engineering and regenerative medicine.

In vivomagnetic resonance imaging of iron oxide-labeled, intravenous-injected mesenchymal stem cells in kidneys of rabbits with acute ischemic kidney injury: detection and monitoring at 1.5 T

“…Using these cells also avoids the ethical ambiguities like using embryonic stem cells. 17 Several previous studies also demonstrated that mesenchymal stem cells could recruit to injured tissue and generate high levels of cytokines and growth factors 18,19 and play a repair role. Therefore, it is interest to determine whether MSCs can be tracked in vivo with non-invasive imaging after AKI stem cells treatment, which will provide a tool for the development and testing of optimal AKI-specific treatment protocols.…”

Three-Dimensional Aggregates of Mesenchymal Stem Cells: Cellular Mechanisms, Biological Properties, and Applications

“…For example, mitogen-activated protein kinase signaling, including ERK1/ 2, p38, and c-Jun N-terminal kinase pathways, are influenced by shear stress through the cell surface signaling to activate the GTPase. 113 Novel design of bioreactors that provide homogenous shear stress may be required in the formation and expansion of MSC aggregates. Spinner flasks displayed heterogeneous shear stress (0-2.83 dyn/cm 2 ), fluid velocity, and Kolmogorov eddy size, which may limit their biological effects on MSCs.…”

A Multicompartment Holder for Spinner Flasks Improves Expansion and Osteogenic Differentiation of Mesenchymal Stem Cells in Three-Dimensional Scaffolds

“…This culture system environment is externally controlled by the incubator environment (O 2 , pH, and humidity) but agitation is controlled in terms of velocity and type of impeller. 2,3 It has been widely explored for the culture of suspension cells, and in some cases for attachment-dependent cells in the form of cell aggregates 4,5 or cell-loaded microcarriers. 3,[6][7][8][9] However, only a few studies described the use of spinner flasks for cell cultures in three-dimensional (3D) scaffolds.…”

“…1,2 Spinner flasks are probably the simplest dynamic culture systems commercially available. They have been used for long times in cell culture, and they are the first step when it comes to scale up the classical two-dimensional (2D) cell culture.…”

“…3,[6][7][8][9] However, only a few studies described the use of spinner flasks for cell cultures in three-dimensional (3D) scaffolds. In those cases, the 3D constructs have been cultured in different ways: (1) maintained in free floating, 10,11 (2) threaded in stacks onto needles embedded in the stoppers of the spinner flask [12][13][14][15] or (3) directly fixed with clamps to the spinner's wall. 16 However, these solutions can damage both the scaffolds and the attached cells and can contribute to an heterogeneous cell distribution.…”