The Effects of Substrate Elastic Modulus on Neural Precursor Cell Behavior

Abstract

The spinal cord has a limited capacity to self-repair. After injury, endogenous stem cells are activated and migrate, proliferate, and differentiate into glial cells. The absence of neuronal differentiation has been partly attributed to the interaction between the injured microenvironment and neural stem cells. In order to improve post-injury neuronal differentiation and/or maturation potential, cell-cell and cell-biochemical interactions have been investigated. However, little is known about the role of stem cell-matrix interactions on stem cell-mediated repair. Here, we specifically examined the effects of matrix elasticity on stem cell-mediated repair in the spinal cord, since spinal cord injury results in drastic changes in parenchyma elasticity and viscosity. Spinal cord-derived neural precursor cells (NPCs) were grown on bis-acrylamide substrates with various rigidities. NPC growth, proliferation, and differentiation were examined and optimal in the range of normal spinal cord elasticity. In conclusion, limitations in NPC growth, proliferation, and neuronal differentiation were encountered when substrate elasticity was not within normal spinal cord tissue elasticity ranges. These studies elucidate the effect injury mediated mechanical changes may have on tissue repair by stem cells. Furthermore, this information can be applied to the development of future neuroregenerative biomaterials for spinal cord repair.

The effect of Young’s modulus on the neuronal differentiation of mouse embryonic stem cells

“…An earlier study [28] demonstrated that the number of primary mixed hippocampal cells positive for MAP2 did not vary with modulus from 1 kPa to 7 kPa. A second study by the same group [92] produced the same result in mixed spinal cord neural precursors. When these spinal cord neural precursor cells were then purified however, the percentage of cells positive for nestin (at D2) and MAP2 (at D5) decreased with an increase in Young's modulus (6 kPa to 27 kPa).…”

Neurite extension and neuronal differentiation of human induced pluripotent stem cell derived neural stem cells on polyethylene glycol hydrogels containing a continuous Young's Modulus gradient

“…Even small changes in substrate properties can lead to significant changes in cellular response . However, many of the previous studies examining the effects of hydrogel Young's modulus on neural differentiation have utilized a few samples over large range of Young's Moduli . The current study uses a continuous Young's Modulus gradient to systematically study the effects of relatively low Young Modulus hydrogels on hNSC response in greater depth (Figs.…”

“…Generally, softer hydrogels with a Young's modulus of ∼1 kPa are thought to be optimal for neural maturation . However, the previous studies have utilized a few discrete samples to determine the optimal Young's Modulus with many selecting the hydrogels with the lowest Young's Modulus tested as the optimal condition, which means the truly optimal Young's Modulus may be outside the studied range.…”

Stiff substrates enhance cultured neuronal network activity

“…Recent studies have evidence to suggest many cells including neurons in the brain are also equipped to sense mechanical cues from their microenvironments such as the stiffness or rigidity of extracellular matrix or cell-supporting substrates, and result in profound effects on their morphology and function1234567891011121314. For instance, substrates with stiffness similar to brain tissues prefer to stimulate neuronal over glial growth in cortical neuronal cultures2.…”

“…Brain injury or neurodegenerative disease can change local or global stiffness of the brain tissues, for example, local tissue stiffness is likely to increase after injury, as a result of formation of structures such as glial scars, and decrease in the brain tissues of patients with Alzheimer's disease and multiple sclerosis15. These and other studies have led to recognition of the mechanical property as an important factor in designing instructive scaffolds for neural tissue engineering101112. A clear understanding of how the mechanical property of neuron-supporting substrates influences neuronal function is still lacking but important in inspiring a full insight into brain function and in particular development of novel neuron-supporting scaffolds for neural tissue engineering or regeneration71012131415.…”