Growth Factors, Matrices, and Forces Combine and Control Stem Cells
Dennis E. Discher1,
David J. Mooney2 and
Peter W. Zandstra3
1 Biophysical Engineering and Nanobiopolymers Laboratory, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA 19104, USA. E-mail: discher{at}seas.upenn.edu
2 Laboratory for Cell and Tissue Engineering, School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138, USA. E-mail: mooneyd{at}seas.harvard.edu
3 Stem Cell Bioengineering Laboratory, Institute of Biomaterials and Biomedical Engineering, Centre for Biomedical and Biomolecular Research, University of Toronto, Toronto, ON M5S 3E1, Canada. E-mail: peter.zandstra{at}utoronto.ca
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Fig. 1. Stem cell niche and designs. (A) Soluble and matrix-bound factors combine with cell-cell contact, cell-matrix adhesion, and gradients to direct cell fate. (B) Substrates with micropatterns of ECM control the size of ESC colonies and pluripotency based on immunofluorescence for the transcription factor Oct4 (in two dimensions, 2D) (7). (Plot): Large islands increase the pluripotent population; small islands inhibit with a time constant of 24 hours. (C) Substrates with microwells help to standardize the diameter of quasi-spherical embryoid bodies (15). Cells and ECM (laminin) exhibit a spherically symmetric pattern (in three dimensions, 3D), with pluripotent cells in the inside.
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Fig. 2. Forces and ECM in stem cell trafficking. (A) To extravasate from the circulation and invade a tissue, stem cells must adhere strongly to the vessel wall and withstand high flow forces. Within a tissue, additional physical factors can direct motile cells, including durotaxis into stiff, fibrotic regions of tissue where cells engraft. (B) Soft tissue elasticity scale ranging from soft brain (72), fat (73), and striated muscle (21), to stiff cartilage [E  20 to 30 kPa at the scale of adhesions (74, 75)] and precalcified bone (21). (C) In vitro substrates that mimic soft and stiff tissue microenvironments (left) show that cells anchor more strongly to stiff substrates, building focal adhesions and actin-myosin stress fibers. (Right) Matrix adhesion and growth factors influence both cell physiology and lineage. Signals from growth factor receptors not only propagate into the nucleus (dashed blue arrow) and direct transcription (black arrow), but also affect Rho-GTPase (guanosine triphosphatase) activity (dotted blue arrow). Rac drives motility forward, and Rho regulates contraction of stress fibers (red), and both can also influence gene expression (dotted red arrow).
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Fig. 3. Synthetic niches in vivo. (A) Materials can fill a specific anatomic defect (pink) to localize transplanted cells and serve as a scaffolding for formation of new tissue. (B) A mandible formed in a patient used a metal and polymer structure that was seeded with MSCs and cytokines (49). (C) A designed material niche maintains stem cell viability and proliferation, while promoting outward migration at an appropriate stage of differentiation. (D) Dispersion of stem cells from a niche into regenerating skeletal muscle (61). (E) Recruitment of host stem cells for subsequent homing to sites of tissue injury. (F) Mice with green fluorescent protein–labeled bone marrow-derived cells (green) show regenerating muscle infiltrated with cells that are dual-labeled for endothelial cell marker CD31 (red), which indicates neovascularization (76).
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