(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 (25), to stiff cartilage (E ~ 20–30 kPa at the scale of adhesions (74)) and pre-calcified bone (25). (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. Schematic (right) shows 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 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).

(A) Soluble and matrix bound factors combine with cell-cell contact, cell-matrix adhesion, and gradients (such as in O₂) to direct cell fate. (B) Substrates with 2D micro-patterns of Extracellular Matrix, ECM, control the size of ESC colonies and pluripotency of ESC based on immunofluorescence for the transcription factor Oct4 (15). Plot: large islands increase the pluripotent population that undergoes self-renewal, while small islands inhibit lead to differentiation with a time constant of 24 hr. (C) Substrates with micro-wells help to standardize the diameter of quasi-spherical, 3D embryoid bodies (21). Cells and ECM (laminin) exhibit spherically symmetric pattern, with pluripotent cells in the inside.

(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 MSC 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 (60). (E) Recruitment of host stem cells for subsequent homing to sites of tissue injury. (F) Mice with GFP bone marrow-derived cells (green) show regenerating muscle infiltrated with cells that are dual-labeled for endothelial cell marker CD31 (red), indicating neo-vascularization (75).