my research

 

graphical abstract

Mechanoadaptation of stem cells drives their behavior towards building tissues in early development and in adult tissue healing

 

 

Imagine the process of the early development. The embryo that develops into who we are today as an individual, originates from a single cell as a result of the fusion between gametes, from the ovum and sperm.

Soon after the fertilization, this single cell, divides rapidly to form the multicellular construct, the morula, blastula, then gastrula. There go the stages of early development where the embryo consists of nothing but a group of naive, non-specialized stem cells. These cells continuously rearrange, compact and reposition themselves across time and length scales to become the tissues, the organs, and finally the whole organism.

The process of embryonic development is indeed magical. The power and the capacity of stem cells to sense and response to all the stimuli presented to them are done with one goal to achieve: to create tissues with specific structure and function. Biochemical, physical, mechanical stimuli are the drivers of the many stem cells behaviour within the embryo. Cells arrange themselves and compact to form the neural tube, which will not be possible without the differential tension across the cell layer. Mechanical stresses play a much more role in dictating of what these stem cells will become, even more than the genes that are present in the cells. because believe it or not, all stem cells of the early embryo share the same genetic information, but somehow at the later stage they are able to migrate to their respective germ layers, and make the template of what will be the future bone/skeletal tissues (mesoderm), or brain, skin (ectoderm), or lung (endoderm)!

So, how do they decide which cells should migrate and which should stay? And which will become the tissue of which germ layers? The answer is indeed the interplay between all the stimuli, that are presented in a gradient throughout the time of the development1. In parallel to this, many works have discovered the role of mechanical stimuli in regulating cell behavior. They used simple defined set of mechanical cues to confirm their role in driving the expression of certain genes that are specific to certain tissues. For example, the expression of osteocalcin that is only specific to bone, and tend to increase when stem cells are stimulated mechanical loading. At the tissue scale, many biological processes are indeed mechanically driven. The shear stress generated from blood flow guides the lining and orientation of endothelial cells in the blood vessel2. This is important for the pulsatile function of blood vessel in mediating blood pumping. Hydrostatic pressure is required in the cartilage interstitial fluid pressurization to support heavy load3.

With growing evidence in the regulatory role of mechanical cues on biological function, the field of “Mechanomics” then emerged from mechanics and biology. It was only discovered 2 decades ago, long enough after “Genomics” was discovered in the late 60s4. Genomics emphasizes on the genetic materials and how they translate into certain features or diseases in an individual. At that time, sequencing of bacterial genome was made possible, so each genome sequence was mapped to its outcome. This led us to believe that all the cellular processes are pre-programmed based on their genetic materials.

In contrast to "Genomics", mechanomics is not pre-programmed. It rather represents the dynamic adaptation of stem cells to their mechanical environment. How those embryonic stem cells sort themselves with regards to their position and future function, is nothing but adaptation to mechanical tension that is presented as gradient across time and length scale in the structure of the developing embryo1. The next stage is then to create the template for the skeleton, the compacted cells again are presented with gradient of differential stresses that create a loosening of their tight connection and consequently initiating cell migration to form the mesenchyme. This is called the EMT, Epithelial to Mesenchymal Transition (shown in figure). The same principle applies in migrating cancer cells during metastasis5. Thus, understanding this process in healthy and in disease can provide valuable insights to promote healthy tissue regeneration and to developing therapies. Studies employing a defined set of mechanical cues, such as exposing cells to high stiffness is well known to guide them to become the hard bone cells, while on low stiffness they tend to become the soft fat cells6.

However, in order to really understand and modulate how tissue develop from a single cell, we need a system that best recapitulate development. The challenge here is the complexity of the mechanical stimuli present in the stem cells environment, which makes it less straightforward to mimic. Combination of complex mechanical cues also result in varying (emergent) cellular (cytoskeleton) responses7, which is basically the consequence of their adaptive behaviour. Thus, if we can figure out how cells adapt while turning on or off their mechanoadaptation machinery during mechanical stimulation, we can understand better cell adaptation to structure and function8. Ultimately, we can use this information to harness stem cells best regenerative capacity and to improve design of tissue engineering devices. Understanding and predicting cell growth and remodelling9 during adaptation to mechanical stimuli that would help improve tissue regeneration!

That is all about my research! Hopefully this will give you insights on the current state of stem cells and tissue engineering research and where the world of mechanobiology is leading to. Please subscribe to my blog to follow me on my journey in this research 😊.

 

 

 

References:
  1. Knothe Tate ML, Falls TD, McBride SH, Atit R, Knothe UR. Mechanical modulation of osteochondroprogenitor cell fate. Int J Biochem Cell Biol. Published online 2008.
  2. Jazayeri M, Shokrgozar MA, Haghighipour N, et al. Evaluation of Mechanical and Chemical Stimulations on Osteocalcin and Runx2 Expression in Mesenchymal Stem Cells. Mol Cell Biomech. 2015;12(3):197-213.
  3. Elder BD, Athanasiou KA. Hydrostatic pressure in articular cartilage tissue engineering: From chondrocytes to tissue regeneration. Tissue Eng - Part B Rev. Published online 2009.
  4. Wang J, Lü D, Mao D, Long M. Mechanomics: An emerging field between biology and biomechanics. Protein Cell. Published online 2014.
  5. Gjorevski N, Boghaert E, Nelson CM. Regulation of epithelial-mesenchymal transition by transmission of mechanical stress through epithelial tissues. Cancer Microenviron. Published online 2012.
  6. Engler AJ, Sen S, Sweeney HL, Discher DE. Matrix Elasticity Directs Stem Cell Lineage Specification. Cell. Published online 2006.
  7. Chang H, Knothe Tate ML. Structure - Function relationships in the stem cell’s mechanical world B: emergent anisotropy of the cytoskeleton correlates to volume and shape changing stress exposure. MCB Mol Cell Biomech. 2011;8(4):297–318.
  8. Putra VDL, Song MJ, McBride-Gagyi S, et al. Mechanomics Approaches to Understand Cell Behavior in Context of Tissue Neogenesis, During Prenatal Development and Postnatal Healing. Front Cell Dev Biol. Published online 2020.
  9. Knothe Tate ML, Gunning PW, Sansalone V. Emergence of form from function—Mechanical engineering approaches to probe the role of stem cell mechanoadaptation in sealing cell fate. Bioarchitecture. Published online 2016.