Mechano-Biological Regulation of Human Mesenchymal Stem Cell Osteogenic Differentiation

Micromotion around bone implant and healing fractures results in the formation of a variety of skeletal tissues instead of bone in locations that are biochemically similar. Mechanical deformation including tensile strain has been implicated in altering the osteogenic potential and subsequent activity of bone marrow derived pluripotent human mesenchymal stem cells (hMSCs), however, the pathway remains unclear.

In this investigation, mechano-biological regulation of hMSC differentiation into the osteogenic lineage was evaluated. Once gradient and biaxial strain loading models were established and characterized, hMSCs, seeded on type I collagen coated silicone elastic membranes, were exposed to cyclic gradient and biaxial strain at 0.1 Hz in the presence and absence of dexamethasone for 2 hours daily up to 21 days.

It was found that the regions of high compression (-3<-2%) and low compression (-2%<0) enhanced extracellular matrix (ECM) mineralization in hMSC cultures without dexamethasone, while regions of low compression (-2<0%), low tension (0<3%), and high tension (3<10%) inhibited ECM mineralization in hMSC cultures with dexamethasone. Biaxial strain (3%) downregulated ALP mRNA expression levels in hMSC cultured with dexamethasone, while production of extracellular matrix decreased, and the accumulation of calcium-containing mineral increased for hMSC cultured in the presence and absence of dexamethasone.

The strain-enhanced progression of hMSCs into the osteogenic lineage was demonstrated by significant decreases in procollagen in conjunction with significant increases in calcium for hMSCs exposed to strain. Maximal expression of osteopontin (OPN) and alkaline phosphatase (ALP) occurred at day 4 and day 5, respectively, for hMSCs exposed to strain. In contrast, the maximal expression of OPN and ALP in hMSCs exposed to control conditions progressed more slowly at day 8 and day 7, respectively. Cyclic strain also demonstrated reorganization of key extracellular components including type I collagen.

Mechanical deformation of hMSCs, in the absence of dexamethasone, increased bone formation. The appearance of osteogenic markers at earlier time points suggests that cyclic strain (0<3%) was capable of accelerating stem cell progression into the osteogenic lineage. The results support and are consistent with predictions made by computational models associating low tensile loading with bone formation around implants and during fracture healing.

Year	Entry
2003	Simmons CA, Matlis S, Thornton AJ, Chen S, Wang C-Y, Mooney DJ. Cyclic strain enhances matrix mineralization by adult human mesenchymal stem cells via the extracellular signal-regulated kinase (ERK1/2) signaling pathway. J Biomech. August 2003;36(8):1087-1096.
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Year

Entry

2003

Simmons CA, Matlis S, Thornton AJ, Chen S, Wang C-Y, Mooney DJ. Cyclic strain enhances matrix mineralization by adult human mesenchymal stem cells via the extracellular signal-regulated kinase (ERK1/2) signaling pathway. J Biomech. August 2003;36(8):1087-1096.

1995

Bay BK. Texture correlation: a method for the measurement of detailed strain distributions within trabecular bone. J Orthop Res. March 1995;13(2):258-267.

1994

Rubin CT, McLeod KJ. Promotion of bony ingrowth by frequency-specific, low-amplitude mechanical strain. Clin Orthop Relat Res. January 1994;298:165-174.

1998

Chow JWM, Wilson AJ, Chambers TJ, Fox SW. Mechanical loading stimulates bone formation by reactivation of bone lining cells in 13‐week‐old rats. J Bone Miner Res. November 1998;13(11):1760-1767.

1997

Jaiswal N, Haynesworth SE, Caplan AI, Bruder SP. Osteogenic differentiation of purified, culture‐expanded human mesenchymal stem cells in vitro. J Cell Biochem. February 1997;64(2):295-312.