The hematopoietic stem cell polarization and migration

Abstract

The polarization and migration of eukaryotic cells are fundamental processes for the development and maintenance of a tissue. These aspects gain especial interest when it comes to stem and progenitor cells in the way that their manipulation might open new avenues in regenerative therapy. In recent years, novel biological facets of migrating hematopoietic stem cells were revealed by several groups including ours. Among these features, the polarization of their membranous (proteins and lipids) and cytoplasmic constituents, which leads to the formation of a specialized sub-cellular structure located at the rear pole – the uropod – has gained increasing interest. In a new study we have demonstrated that such phenomena involve a coordinated mechanism between Rho GTPase signaling and the microtubule network. Specifically, our results based on the use of synthetic inhibitors and RNA interference suggest that the activity of RhoA and its effector ROCK I is indispensable for cell polarization and the active reorganization of microtubules that are required for migration.

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Acknowledgements

We thank C.A. Fargeas for critically reading the manuscript. This work was supported by grant from Deutsche Forschungsgemeinschaft (SFB 655 B3, SFB/TRR83 No.6).

Figures and Tables

Figure 1 RhoA/ROCK I pathway and remodeling of microtubule network underlie the polarization and migration of HSPCs. (A) A migrating HSPC growing on MSC displays a polarized morphology with the formation of a uropod (U) at the rear pole and a leading edge (LE) at the front. Both types of plasma membrane protrusions contain a specific ganglioside-based membrane microdomain—the uropod being enriched in GM₁ (red) whereas the leading edge in GM₃ (green). In addition to prominin-1, a plethora of cell adhesion molecules (inset) including PSGL-1 are concentrated in the uropod whereas the chemokine receptor CXCR4 is found at the leading edge consistent with its sensory role towards an SDF-1α gradient.6 ERM proteins seem to be actively involved in the subcellular localization of some uropod-associated membrane proteins.18 Other molecules such as CD34 and CD45 are evenly distributed. The microtubule-organizing centre is found between the nucleus and the uropod. (B) The activity (↓) of RhoA and its downstream effector ROCK I contributes to the formation of the uropod, and hence polarization and migration of HSPCs. The downstream target(s) remain to be identified (?), but it might engage a protein involved in microtubule destabilization (dashed green line). (C) Inhibition (⊥) of ROCKs using Y-27632 or the specific knockdown of ROCK I or its upstream regulator RhoA by means of RNAi results in an elongated morphology where the uropod is lost. Both membrane (prominin-1, PSGL-1) and cytoplasmic (ezrin) proteins are redistributed. These cells display an impairment of migration caused by microtubule stability (solid green line). (D) In RhoA/ROCKI-deficient HSPCs, the addition (+) of nocodazole restores their proper polarization and migration highlighting the implication of unidentified microtubule-destabilizing proteins. Green and red arrows indicate the direction of migration.

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