Impact of substrate elasticity on human hematopoietic stem and progenitor cell adhesion and motility

Abstract

SummaryIn the bone marrow, hematopoietic stem cells (HSCs) reside in endosteal and vascular niches. The interactions with the niches are essential for the maintenance of HSC number and properties. Although the molecular nature of these interactions is well understood, little is known about the role of physical parameters such as matrix elasticity. Osteoblasts, the major cellular component of the endosteal HSC niche, flatten during HSC mobilization. We show that this process is accompanied by osteoblast stiffening, demonstrating that not only biochemical signals but also mechanical properties of the niche are modulated. HSCs react to stiffer substrates with increased cell adhesion and migration, which could facilitate the exit of HSCs from the niche. These results indicate that matrix elasticity is an important factor in regulating the retention of HSCs in the endosteal niche and should be considered in attempts to propagate HSCs in vitro for clinical applications.

Biophysical regulation of hematopoietic stem cells

“…[80][81][82] They exhibit an amoeboid-type migration behaviour, which leads to a fast migration speed of several µm per minute. 54 These phenomenological observations in 2D cell culture systems indicate a more transient nature of integrin-mediated contacts between ECM molecules and HSCs, compared to contacts with anchorage-dependent cells.…”

“…Nevertheless, many of the substrates that were shown to elicit mechanosensitive responses in HSCs do actually target integrins. 52,54,62 This suggests that, similar to their role in anchorage-dependent cells, integrins are likely to act as environmental sensors in HSCs, even though the composition and maturation of the associated multiprotein complexes might differ. These differences are accompanied by some striking phenomenological differences between HSCs and anchoragedependent cells.…”

“…When PI3K is specifically inhibited, adhesion and motility on stiff matrices are reduced down to a level similar to that observed on soft matrices. 54 Which signals act up-and downstream of PI3K remains to be elucidated. Another particularly interesting potential mechanosensor located downstream of integrins is the adaptor molecule P130CAS, which undergoes conformation changes under mechanical stretching.…”

Challenges and Opportunities to Harnessing the (Hematopoietic) Stem Cell Niche

“…Changes in stiffness of 2D material surfaces have been linked to significant changes in HSC morphology [31] and motility [63]. When cultured on type I collagen-coated polyacrylamide gels with varying stiffness (0.71–196 kPa), HSCs spread out more and appeared less circular on stiffer substrates, exhibiting more irregular morphology [31].…”

“…When cultured on type I collagen-coated polyacrylamide gels with varying stiffness (0.71–196 kPa), HSCs spread out more and appeared less circular on stiffer substrates, exhibiting more irregular morphology [31]. On fibronectin-coated PEGDA substrates, HSCs adhered better and migrated faster to a chemotactic cue on stiffer (>38 kPa) vs. softer (≤20 kPa) substrates [63]. These studies suggest that HSCs are responsive to changes in mechanical cues, but more studies should be performed to assess how such cues lead to definitive functional changes in cultured HSCs (e.g., proliferation, differentiation).…”