Biography
Interests
Osama S. Abbadi1* & Ayoub A. Mohamed2
1Department of Biochemistry, Faculty of Medicine, Omdurman Islamic University, Sudan
2Department of Medicine, Section of Infectious Diseases, King Abdulaziz Medical City, Riyadh, Saudi
*Correspondence to: Dr. Osama S. Abbadi, Department of Biochemistry, Faculty of Medicine, Omdurman Islamic University, Sudan.
Copyright © 2019 Dr. Osama S. Abbadi, et al.. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Physical forces affect homeostasis. The recent advances in molecular techniques and tissue assays allowed the science to measure these effects at the level of proteins, growth factors, and gene expression. In this short review, we report the experimental work done by molecular biologists with regard to the molecular changes in response to four different types of physical stimuli: stretch, fluid flow, fluid pressure, and negative pressure.
Abbreviations
Ang-2: Angiogenin type 2; a vascular growth factor.
INP: Intermittent negative pressure.
FAK: Focal adhesion kinase.
MSCs: Mesenchymal stem cells.
PDGF- ββ: Platelet-derived growth factor beta-beta.
Rac-1: Ras-related C3 botulinum toxin substrate 1 (a cell cycle regulatory pathway).
Ras: A signaling protein; (discovered in rat sarcomas)
Introduction
Cells could divide, differentiate, transfer, or even die in response to physical stimulus, and the improper
response to these stimuli leads to pathologies [1]. For an organism to survive, it should pass the test of
adaptation to physical forces [2]. The strategy to and magnitude of this response differs from an organism
to another, and the difference is more obvious when comparing unicellular organisms to multi-cellular
organisms [3]. When the mechanical stimulus is translated into a chemical cell signal, the process is called
mechanotransduction [4,5,6]. The molecular pathways that represent the response cascade to mechanical
power are referred to as mechanosensing pathways. Various mechanical forces had been tested to study their
effects on the living tissues, and these include: mechanical stretch, fluid flow, fluid pressure, and negative
pressure.
Mechanical Stretch
Studies showed that tissues and cells could be stimulated to grow faster in vitro when subjected to a suitable
stretch power, as documented by Powell et al on engineered skin [7], and Lee et al on organ culture arteries
[8]. Yung et al (2009) demonstrated the effect of stretch on vessels by applying cyclical strain on human
umbilical vein; it did activate vascular growth factors production and the expression of the cytokines (Ang-
2) and (PDGF-ββ) [9]. A good target for biomechanical stimulation is mesenchymal cells, because they are
capable to differentiate into many types of cells [10,11]. Aiming to produce cardiac smooth muscle tissue,
Park et al searched on (2004) the possibility of giving rise to smooth muscle cells from the mesenchymal
stem cells (MSCs) of the bone marrow [10]. They concluded that strain on one direction could induce
smooth muscle differentiation from bone marrow mesenchyme, unlike multidirectional straining, which
gave a disappointing result [10]. Also in (2004), Hamilton, Maul, and Vorp explained the possibility of
harvesting smooth muscle cells from progenitor cells of rat’s bone marrows through cyclic strain; daughter
cells were well aligned and expressed smooth muscle cells Actin filaments [12]. Nieponice et al concluded
on (2007) that cyclic stretch further accelerated the conversion of bone marrow progenitor cells into smooth
muscle cells, smooth muscle markers were up-regulated, and Collagen amount rose [13]. In (2008), Zhang
et al concluded, through experiments on rat bone mesenchymal cells, that stretch to one direction increases
the expression of type I and type III collagens; the most abundant collagens [11], and Tenascin-C protein;
an extracellular matrix glycoprotein protein that modulates cell adhesion and morphology [11,14]. Cells of
mesenchyme also gained a more elongated figure [11]. A remarkable comparative study was performed by
Maul et al in (2011); it compared the effects of cyclic stretch, cyclic hydrostatic pressure, and laminar shear
stress on mesenchymal stem cells [15]. Results confirmed that the mechanical cues could change the shape
of mesenchymal cells, affect their size, and modify their configuration [15]. Cyclic stretch, in particular, leads
to the expression of smooth muscle cell proteins markers and muscle genes, while the hydrostatic pressure
and the shearing stress were in favor of activating endothelium genes [15].
Fluid Flow
The mechanotransduction in the vascular cells; endothelial cells, fibroblasts, and smooth muscle cells, and
their coordination to maintain an optimum vascular function, was researched in details [16]. Shear stress
gives the endothelial cells a spindle shape and a well organized manner at the same direction of the stream
[15,16]. It shifts the smooth muscle cells into the protein synthesis pathways [16]. Ting et al (2012) stated
that regular laminar flow gives rise to bigger cell junctions when compared to a disorganized flow medium
and the structural proteins are organized parallel to the current direction [17]. Literature revealed that cellular
responses to abnormal hydro-mechanical conditions are fundamental in the etiology of atherosclerosis
[18,19]. The normal blood flow inhibits pro-inflammatory mediators, while the disturbed, plaque-mediated
flow does not; hence leukocytes-mediated inflammatory response occurs and progresses into the fully
developed atherosclerotic vessel, and the smooth muscles thin out because they are not stimulated by cyclic
stretch, which is masked due to the preformed plaque [18].
Fluid Pressure
A mechanical stimulation particularly related to the bladder is the cyclic hydrodynamic pressure. The process
of emptying and refilling of the bladder has its role in proliferation and preservation of the function
of smooth muscle cells of the bladder. Wu et al (2012) researched, on a cell culture, the activity status of
the Rac-1 cellular signaling pathway, which is an important pathway in cell division control [20]. Results
showed that Rac-1 was activated in response to the hydrodynamic pressure, among other Protein kinases,
and the smooth muscles of the bladder cells were dividing in a remarkably accelerated manner [20]. Wei
et al examined, in (2014), the protein Integrin’s role in the proliferation of bladder smooth muscle cells in
a hydrodynamic pressure medium [21]. Integrin is a signal mediator of growth and proliferation, amongst
many other cellular modulating functions [22]. The cyclic hydrodynamic pressure had lead to activation of
cell division, induction of the synthesis of Integrin, and phosphorylation of focal adhesion kinase-FAK, the
main regulator of Integrin-dependent pathways [21]. Recently in (2017), Chen et al studied bladder tissues
responses to another mechanical stimulus; stretch, and they targeted mainly the extracellular matrix (ECM)
proteins [23]. Results showed that expression of collagens I and III were up-regulated, and the FAK-dependent
Integrin pathway is presumed to be a responsible factor [23].
Negative Pressure
It is simply defined as a pressure less than the normal atmosphere. It is found normally in the body at the
lung, as an important factor for respiration [24]. At the tissue level, there were few trials to document the
effects of negative pressure in the sub-cellular and molecular level. Zhang et al (2010) worked on MSCs and
studied how intermittent negative pressure, (INP), could determine their offspring and velocity of division
[25]. They applied a half an hour INP of low magnitude; unexpectedly, cell division was inhibited, apoptosis
(programmed cell death), was higher than usual, and collagen-I was over-expressed [25]. On 2014, Yang
et al operated a similar study on MSCs, and concluded that cells shifted toward apoptosis, over-expressed
type I collagen and alkaline phosphatase (ALP), and activated osteoblast formation [26]. Sun et al (2017)
studied the possible effect of INP in accelerating the healing on a post-operative anterior cruciate ligament
in a rabbit [27]. The experiment showed accelerated osteogenesis and reduction in the inflammatory markers
TNF-α and IL-1β in the group underwent INP. The study supported that INP could promote the healing
at the junction of bone and tendon [27].
Discussion
From the above studies, it is obvious that mechanical forces are generally in favor of tissue growth enhancement
and proliferation, with the exception of negative pressure which had explicitly induced cellular death.
Stretch power proved to enhance selective differentiation of MSCs, particularly to smooth muscle cell type.
Stretch mechanics is a promising method in the skin graft and wound management. The regular vascular
flow maintains the shape and alignment of the vascular endothelium, in contrast to the disrupted flow,
which favors the formation of plaques and, consequently, atherosclerosis. Maintaining the straight flow is
protective against thromboembolic phenomenon. Fluid pressure proved to augment the bladder epithelial
proliferation, and expression of Integrins. It is fair to say that the above three mechanical factors promote tissue proliferation and maintenance, the stretch force being the most potent modality. Negative pressure,
on the other hand, gave paradoxical outcome, being in favor of apoptosis and, at the same time, fastening
wound healing and promoting collagen expression. Negative pressure, apart from the respiratory mechanics,
is not a normally occurring physical phenomenon, while fluid and stretch mechanics are concomitant with
the biological processes. Scientists tend to use INP in their trials rather than the use of sustained negative
pressure. This is basically to avoid the accumulation of fluid and inflammatory cells. A couple of researches
were performed in cancer cells with regard of INP effect in the growth inhibition, two results were in favor
of apoptosis [25,26], and one stated that malignant cells became more aggressive [28]. Negative pressure use
will be beneficial in chronic wounds management, burn scar management, and cancer studies, particularly
skin cancer.
Conclusion
Physical powers; stretch, fluid flow, hydrostatic pressure and negative pressure, affect cellular proliferation,
protein expression, and tissue configuration. The outcome of these powers ranges between tissue proliferation
enhancement and cell death. INP might have an impact in Cancer treatment studies.
Bibliography
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