How the mechanical microenvironment of stem cell growth affects their differentiation: a review

Abstract

Stem cell differentiation is of great interest in medical research; however, specifically and effectively regulating stem cell differentiation is still a challenge. In addition to chemical factors, physical signals are an important component of the stem cell ecotone. The mechanical microenvironment of stem cells has a huge role in stem cell differentiation. Herein, we describe the knowledge accumulated to date on the mechanical environment in which stem cells exist, which consists of various factors, including the extracellular matrix and topology, substrate stiffness, shear stress, hydrostatic pressure, tension, and microgravity. We then detail the currently known signalling pathways that stem cells use to perceive the mechanical environment, including those involving nuclear factor-kB, the nicotinic acetylcholine receptor, the piezoelectric mechanosensitive ion channel, and hypoxia-inducible factor 1α. Using this information in clinical settings to treat diseases is the goal of this research, and we describe the progress that has been made. In this review, we examined the effects of mechanical factors in the stem cell growth microenvironment on stem cell differentiation, how mechanical signals are transmitted to and function within the cell, and the influence of mechanical factors on the use of stem cells in clinical applications.

Keywords: Extracellular matrix; HIF-1α; Hydrostatic pressure; Microgravity; NF-kB; PIEZO; Shear stress; Stem cell; Tension; nAChR.

Fig. 1

Mechanical stimulation regulates the differentiation of stem cells into osteoblasts/osteoclasts and chondroblasts through the NF-κB pathway. Mechanical stretching can reduce phosphorylated IκB kinase, block NF-κB activity, and promote osteogenic differentiation of cells. Fluid shear stress also increases the expression of OPG, the decoy receptor for RANKL, upregulating the expression of osteoblast marker genes. Mechanical loading can reduce the levels of IL-1β, which in turn reduces NF-κB expression and regulates the chondrogenesis

Fig. 2

Mechanistic effects attenuate stem cell osteogenic differentiation via the nAchR signalling pathway. Under stress, TNF-α and IL-1β increase phosphorylated GSK-3β in stem cells, which then promotes the expression of α7 nAChR. nAChR is activated by the ligand Ach, which in turn upregulates RANKL and downregulates genes related to osteogenic differentiation

Fig. 3

Mechanical stimulation induces osteogenic differentiation of stem cells via the PIEZO pathway. Mechanical stimulation induces cilia, which causes Ca²⁺ to enter the cell via PIEZO, activating the Notch signalling pathway and upregulating osteogenic differentiation genes. Mechanical damage also phosphorylates p38 MAPK via the IL-1α receptor, activating the transcription factor CREBP, which binds to the PIEZO gene promoter and can upregulate PIEZO

Fig. 4

Maintenance of stem cell osteogenic factor homeostasis and maintenance of chondrocyte phenotype through the HIF-1 pathway. HIF-1α increases TWIST expression, which in turn regulates osteogenic differentiation. Mechanical stimulation also promotes TWIST and inhibits E2A; TWIST and E2A interact to activate p21. p21 has different regulatory effects on osteogenic factors. Also, p21 positively regulates the expression of TWIST and negatively regulates the expression of E2A. Hypoxia and HIF-1α maintain the chondrogenic phenotype of cells by preventing cell osteogenic differentiation