Reappraising the role of α5 integrin and the microenvironmental support in stress erythropoiesis

Abstract

TU performed all experiments, evaluated the results, and wrote relevant sections of the article. GG performed bioinformatic evaluations. TP designed experiments, evaluated data, and wrote the article.

Gene Expression Analysis of Mevalonate Kinase Deficiency Affected Children Identifies Molecular Signatures Related to Hematopoiesis

“…In particular, α4 integrins, which are expressed on erythroid cells, have been reported to affect terminal erythroid maturation under stress. A significant impairment of stress response is observed in the absence of α4 integrin [38,39]. This is consistent with our observation of lower levels of integrin α4 in PBMC from MKD patients.…”

α4-Integrin deficiency in human CD34+ cells engenders precocious erythroid differentiation but inhibits enucleation

“…Whereas virtually all of the in vivo data concerned murine hematopoiesis, in vitro data on a4 influence on proliferation of either murine or human progenitor cells have been controversial with either positive [5−11] or negative influence [12−18] depending on the presence of in vitro ME interactions and varying experimental settings. By contrast, a4 influence on later cells participating in erythroid terminal differentiation has been more consistent at least for murine data, both in vivo [1,19,20] and in vitro [21]. Further, certain molecules with decisive influence on erythroid cell maturation have also been described to exert their influence through modulation of a4 integrins [22].…”

“…Furthermore, it is unclear whether in vivo ME interactions provide a compensatory outcome. In this context, although inhibition of a4-dependent proliferation was described during in vivo in fetal erythropoiesis [1,19] and in adult life in stress erythropoiesis, steady-state hematopoiesis was not perturbed by either specific a4 deficiency [4,20] or FAK inactivation [51].…”

“…Its expression at several maturation stages has been exploited to discriminate the stage of maturity in human erythroid cells [26]. Although the dominant importance of a4 integrin has been noted above, its relationship with a5 integrin in erythropoiesis has been found to be complex and incongruous, ranging from synergistic at early stages [20] to antagonistic or inert [5,6,12,17,27] depending on the experimental conditions through the use of antibodies, crosslinking experiments, or several knockdown approaches.…”

Matrix Mechanosensation in the Erythroid and Megakaryocytic Lineages

“…Inhibiting VLA-4 engagement with fibronectin blocked erythroid development; however, blocking VLA-5 in the same fashion did not have the same affect [42]. The roles of the two predominate fibronectin integrins on erythroid progenitors are debated, as it has not always been clear from in vivo models what distinct functions these fibronectin-binding integrins serve [43][44][45]. This raises the possibility that the stiffness of fibronectin used in the different studies could influence the effect of these integrins on erythroid differentiation.…”