1. Mechanical Regulation of Mesenchymal Stem Cell Regulation
Tissue Engineering
Lecture 10, 3/10/15
Paper Review
Mechanical Regulation of Mesenchymal Stem Cell Regulation

2. What is the motivation of this study?
This article came out in 2014, and it attempts to give a global overview of how different mechanical forces impact stem cell behavior.
This will help new students, and new faculty, in this area get a grasp of “where the field is now” before they start their experiments.
They give an overview of all the different types of mechanical forces that impact stem cell behavior.
They also give some mechanistic information on what internal components of the cells are responsible for translating mechanical cues into biochemical signals.

3. Figure 1: Akarawin Hongdusit

4. Figure 1: Akarawin Hongdusit, Extra Slide 1

5. Figure 1: Akarawin Hongdusit, Extra Slide 2

6. Biomaterials overview
Fibronectin-coated PDMS
Collagen-coated poly(acrylamide) OH OH OH
UVO, 30min
3D Poly(ethylene glycol)
3D alginate

7. Table 1 (through Huebsch): Jonathan Hummel

8. Table 1 (Pek through Steward): Michael Mulroy

9. Possible mechanotransducing elements
Compression
Tension
Fluid Flow
Pressure
Shape
Substrate Stiffness

10. Table 2 (fluid flow and hydrostatic pressure):
Hiu Yeung

11. Table 2 (fluid flow and hydrostatic pressure):
Hiu Yeung

12. Table 2 (Compression): Brittany Shepler

13. Brittany Shepler, cont.

14. Table 2. Tension (Singyuk Hou)
Application of tensile strain to cultured MSCs
Effect of tension
Osteogensis
BMP-2
Calcium deposition
Osteogenic mRNA
IL-6 and IL-8
ERK
Collagen 1
Osteopontin
Osteocalcin
ALP activity
P38,PI3
Cbfa-1, Ets-1
Chondrogensis
sGAG synthesis rate
Stretch-activated calcium channel

15. Osteogenesis Materials formation from differentiated MSCs:
Calcium phosphate (Hydroxyapatite): Major inorganic component of bone
Collagen 1: Main organic component of bone,
served as nucleation site for mineral components.
Osteocalcin: Protein hormone
secreted by osteoblast,
marker associated with mineralization
Osteopontin: Protein binding to
cell surface receptors,
other matrix proteins and
calcium deposits, involved in
osteopontin-cell adhesion,
signaling and hydroxyapatite
crystal formation
BMP-2 (Bone morphogenic protein-2):
Protein belonging to TGF-alpha family, a hormone
secreted by osteoblast to stimulate formation
of bone

16. Enzyme activities in differentiated MSCs (All up-regulated)
ALP ( Alkaline Phosphatase): Key enzyme that provides high concentrations of phosphate at the site of mineral deposition; Maker for osteoblast.
ERK(Extracellular signal-regulated kinase):
Kinase belonging to MAPK (mitogen-activated
protein kinase) family,
involved in MAPK signaling pathway
p38 and PI3: Kinases belonging to MAPK family
Transcription factors expression
differentiated MSCs:
Cbfa-1 (RunX) and Ets-1: Play important roles
in regulating the expression of a wide variety
of genes responsible for the osteoblast
phenotype including osteocalcin, osteopontin,
type I collagen and ALP
Int J Biol Sci 2012; 8(2):

17. Secretion of molecules from other cells:
IL6: Cytokine secreted by T cells and macrophages 
to stimulate immune response
IL8: Chemokine produced by macrophages,
epithelial cells, airway smooth muscle cells,
endothelial cells and so forth
They :
---Bind to RANKL
---Inhibit bone resorption (decomposition
of bone minerals and collagen into blood)

18. Chondrogensis
sGAG (sulphated glycosaminoglycan) : Chondrocytes secret chondroitin ( sGAG)
to produce and maintain the cartilaginous matrix, rate of sGAG synthesis is marker
for chondrogenic differentiation of MSCs
Stretch-activated calcium ion channel: Regulating intracellular calcium level. sGAG synthesis
Rate is dependent on the ion channel.

19. Figure 2: Christine Davis

20. Conclusions, Perspectives
Mechanical forces on stem cells includes static stiffness and active loading.
Various cell-surface receptors are mechano-sensitive, transduced to stem cell behavior through the cytoskeleton.
We still don’t fully understand what the mechanical environment is like in vivo.
Most studies are isolating 1 force at a time, likely not the case in vivo.

21. Grant Teams Soon!
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