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Matrix compliance and RhoA direct the differentiation of mammary progenitor cells

Biomechanics and Modeling in Mechanobiology volume 11, pages 1241–1249 (2012)Cite this article

Abstract

The regenerative capacity of the mammary gland following post-lactational involution depends on the presence of multipotent stem or progenitor cells. Mammary progenitor cells exist as a quiescent and self-renewing population capable of differentiating into luminal epithelial and myoepithelial cells and generating ductal and alveolar structures. The fate choices of these cells are regulated by several soluble signals as well as their surrounding extracellular matrix. Whereas matrix stiffness has been implicated in organ-specific differentiation of embryonic and mesenchymal stem cells, the effects of substratum compliance on the more limited fate switches typical of tissue-specific progenitor cells are unknown. Here, we examined how the mechanical properties of the microenvironment affect the differentiation of mammary progenitor cells. Immortalized human mammary progenitor cells were cultured on synthetic hydrogels of varying stiffness, and their self-renewal and fate decisions were quantified. We found that cells cultured on soft substrata differentiated preferentially into luminal epithelial cells, whereas those cultured on stiff substrata differentiated preferentially into myoepithelial cells. Furthermore, pharmacological manipulations of cytoskeletal tension in conjunction with analysis of gene expression revealed that mechanical properties of the microenvironment signal through the small GTPase RhoA and cytoskeletal contractility to modulate the differentiation of mammary progenitor cells. These data suggest that subtle variations in the mechanical compliance of a tissue can direct the fate decisions of its resident progenitor cells.

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Abbreviations

ECM:

Extracellular matrix

ES:

Embryonic stem

FAK:

Focal adhesion kinase

MLCK:

Myosin light chain kinase

MSCs:

Mesenchymal stem cells

PA:

Polyacrylamide

ROCK:

Rho-associated kinase

TDLU:

Terminal ductal lobular unit

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Affiliations

  1. Department of Chemical and Biological Engineering, Princeton University, Princeton, NJ, 08544, USA

    Cecillia Lui, KangAe Lee & Celeste M. Nelson

  2. Department of Molecular Biology, Princeton University, Princeton, NJ, 08544, USA

    KangAe Lee & Celeste M. Nelson

Authors
  1. Cecillia Lui
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  2. KangAe Lee
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  3. Celeste M. Nelson
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Correspondence to Celeste M. Nelson.

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Lui, C., Lee, K. & Nelson, C.M. Matrix compliance and RhoA direct the differentiation of mammary progenitor cells. Biomech Model Mechanobiol 11, 1241–1249 (2012). https://doi.org/10.1007/s10237-011-0362-7

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  • DOI: https://doi.org/10.1007/s10237-011-0362-7

Keywords

  • Mammary stem cells
  • Differentiation
  • Matrix compliance
  • RhoA
  • Mechanical stress
  • Branching morphogenesis