Mechanical modulation of osteochondroprogenitor cell fate

Abstract

Mesenchymal cells are natural tissue builders. They exhibit an extraordinary capacity to metamorphize into differentiated cells, using extrinsic spatial and temporal inputs and intrinsic algorithms, as well as to build and adapt their own habitat. In addition to providing a habitat for osteoprogenitor cells, tissues of the skeletal system provide mechanical support and protection for the multiple organs of vertebrate organisms. This review examines the role of mechanics on determination of cell fate during pre-, peri-and postnatal development of the skeleton as well as during tissue genesis and repair in postnatal life. The role of cell mechanics is examined and brought into context of intrinsic cues during mesenchymal condensation. Remarkable new insights regarding structure function relationships in mesenchymal stem cells, and their influence on determination of cell fate are integrated in the context of de novo tissue generation and postnatal repair. Key differences in the formation of osteogenic and chondrogenic condensations are discussed in relation to direct intramembranous and indirect endochondral ossification. New approaches are discussed to elucidate and exploit extrinsic cues to generate tissues in the laboratory and in the clinic.

Emergence of form from function—Mechanical engineering approaches to probe the role of stem cell mechanoadaptation in sealing cell fate

“…Specifically, stem cells exhibit more than a thousand fold greater capacity to sense and adapt to their local mechanical environment than differentiated cells of musculoskeletal and vascular lineages. [3][4][5][6][7][8] Specifically, stem cells upregulate transcription and secretion of structural proteins in response to short duration (minutes to an hour), subtle mechanical cues (1000x smaller in magnitude compared to those experienced by terminally differentiated cells). Such subtle mechanical cues arise e.g.…”

“…from force transduction associated with cell proliferation and motility in early developmental periods, before the first beat of the heart or twitch of skeletal muscle. 3 Cytoskeletal protein remodeling shows similar plasticity in response to changes in the stem cells prevailing mechanical environment. 6,8 Remarkably, the "astonishing.…”

“…[10][11][12] In addition, stem cells modulate their own environment by altering their own structure as well as modulating emergent tissue architectures through up and down regulation of cytoskeletal, adhesion, and ECM protein transcription. 4,8 Although many published studies have addressed structure-function relationships in either terminally differentiated cells 5,6,13,14 or at mid-late stages of embryonic development where vascular pressure gradients 15,16 and/or muscle forces can be either measured or estimated, 3,17,18 very few studies have probed the mechanome at earliest stages of fate initiation or in live cells. [3][4][5][6][7][8] The interplay of chemical and physical cues on stem cell differentiation comprises a current topic of intense study.…”

“…10 Loss in junctional proteins favors a motile phenotype, enabling the cell to leave its current milieu and to become adherent in a new niche, where it may then lay down a matrix and become immotile once again. 3,[33][34][35] Osteocytes and red blood cells may represent two terminally differentiated phenotypes where the cell is so highly specialized that the probability of transdifferentiation is very low if not statistically impossible. 3 Taken in context of epithelial to mesenchymal (EMT) and mesenchymal to epithelial transitions (MET), which serve as archetypes for cell mediated tissue genesis during prenatal development and postnatal healing, the genesis of ECM by stem cells may play a decisive role in sealing stem cell fate.…”

“…3,[33][34][35] Osteocytes and red blood cells may represent two terminally differentiated phenotypes where the cell is so highly specialized that the probability of transdifferentiation is very low if not statistically impossible. 3 Taken in context of epithelial to mesenchymal (EMT) and mesenchymal to epithelial transitions (MET), which serve as archetypes for cell mediated tissue genesis during prenatal development and postnatal healing, the genesis of ECM by stem cells may play a decisive role in sealing stem cell fate. Indeed, the very foundation of tissue genesis depends on initial arrangements of cells in space and time, 10 resulting in patterning of the organism's template in prenatal development and a tissue template in postnatal healing.…”