Extrinsic modulation of integrin α6 and progenitor cell behavior in mesenchymal stem cells.

Nuria Nieto-Nicolau,Oscar Fariñas,Andrés Savio,Raquel M De La Torre,Ricardo P Casaroli-Marano,Anna Vilarrodona

doi:10.1016/j.scr.2020.101899

Nuria Nieto-Nicolau, Oscar Fariñas + Show 4 more

Open Access

https://doi.org/10.1016/j.scr.2020.101899

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Abstract

Mesenchymal stem cells (MSC) are heterogeneous cells of complex nature that show different potentials while different culture conditions can modify their functionalities through interactions with the microenviroment. Here, we found that bone marrow (BM) MSC from different donor sources and passages that expressed higher levels of α6 integrin subunit (ITGA6), showed higher clonogenicity, migration and differentiation potential. ITGA6 showed important roles improving these potentials and regulating proliferation through protein kinase B (AKT) pathway and cell cycle inhibitor proteins p53 and p21. Moreover, ITGA6 downregulation impaired migration. Cell confluence regulated ITGA6, increasing its expression in low density cultures and decreasing in high density cultures. Besides, ITGA6- cells expressed ITGA6 when seeded at low densities. We found higher ITGA6 expression on fibronectin substrates at lower confluency. Fibronectin increased proliferation, clonogenicity, activation of AKT, decreased cell cycle inhibitor proteins and augmented growth factors expression. Spheres-derived MSC showed higher ITGA6 expression and enhanced potentials for migration, clonogenicity and proliferation. In conclusion, though there is an intrinsic regulation of ITGA6 expression, associated to the progenitor potential of BM-MSC, this expression is regulated by culture conditions and is translated in changes in cell behavior and proliferation. This knowledge could be used to enhance the potential of BM-MSC for clinical application.

Highlights

Mesenchymal stem cells (MSC) have emerged as a promising tool for tissue engineering because their capability to differentiate toward various lineages (Liu et al, 2009)
Though there is an intrinsic regulation of Integrin alpha 6 (ITGA6) expression, associated to the progenitor potential of bone marrow mesenchymal stem cells (BM-MSC), this expression is regulated by culture conditions and is translated in changes in cell behavior and proliferation
Our results suggest the existence of an intrinsic regulation of ITGA6 associated to the progenitor potential, and a microenvironmental regulation of ITGA6 expression, that is translated in a modulation of cell cycle proteins, proliferation, differentiation, migration and clonogenicity

Summary

Introduction

Mesenchymal stem cells (MSC) have emerged as a promising tool for tissue engineering because their capability to differentiate toward various lineages (Liu et al, 2009). These cells are accessible somatic stem cells that can be isolated. MSC are a heterogeneous population of cells with different capabilities (Colter et al, 2001) and MSC from different donors or somatic sources can have different capacities (Alt et al, 2012; Zaim et al, 2012; Zhu et al, 2009) The characterization of optimal culture conditions to enhance the potential of MSC is of great significance

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