Hyaluronan modulates growth factor induced mammary gland branching in a size dependent manner

Cornelia Tolg, Han Yuan, Sarah M. Flynn, Kaustuv Basu, Jenny Ma, Kenneth Chor Kin Tse, Beatrice Kowalska, Diana Vulkanesku, Mary Cowman, James B. McCarthy, Eva A. Turley

Research output: Contribution to journalArticle

Abstract

Mammary gland morphogenesis begins during fetal development but expansion of the mammary tree occurs postnatally in response to hormones, growth factors and extracellular matrix. Hyaluronan (HA) is an extracellular matrix polysaccharide that has been shown to modulate growth factor-induced branching in culture. Neither the physiological relevance of HA to mammary gland morphogenesis nor the role that HA receptors play in these responses are currently well understood. We show that HA synthase (HAS2) is expressed in both ductal epithelia and stromal cells but HA primarily accumulates in the stroma. HA accumulation and expression of the HA receptors CD44 and RHAMM are highest during gestation when gland remodeling, lateral branch infilling and lobulo-alveoli formation is active. Molecular weight analyses show that approximately 98% of HA at all stages of morphogenesis is >. 300. kDa. Low levels of 7-114. kDa HA fragments are also detected and in particular the accumulation of 7-21. kDa HA fragments are significantly higher during gestation than other morphogenetic stages (p <. 0.05). Using these in vivo results as a guide, in culture analyses of mammary epithelial cell lines (EpH4 and NMuMG) were performed to determine the roles of high molecular weight, 7-21. kDa (10. kDa MWavg) and HA receptors in EGF-induced branching morphogenesis. Results of these assays show that while HA synthesis is required for branching and 10. kDa HA fragments strongly stimulate branching, the activity of HA decreases with increasing molecular weight and 500. kDa HA strongly inhibits this morphogenetic process. The response to 10. kDa HA requires RHAMM function and genetic deletion of RHAMM transiently blunts lateral branching in vivo. Collectively, these results reveal distinct roles for HA polymer size in modulating growth factor induced mammary gland branching and implicates these polymers in both the expansion and sculpting of the mammary tree during gestation.

Original languageEnglish (US)
JournalMatrix Biology
DOIs
StateAccepted/In press - Oct 25 2016

Fingerprint

Hyaluronic Acid
Human Mammary Glands
Intercellular Signaling Peptides and Proteins
CD44 Antigens
Morphogenesis
Breast
Molecular Weight
Pregnancy
Extracellular Matrix
Polymers
Stromal Cells
Fetal Development
Epidermal Growth Factor
Polysaccharides
Epithelium
Epithelial Cells
Hormones

Keywords

  • Branching morphogenesis
  • CD44
  • Hyaluronan
  • Hyaluronan fragments
  • Mammary gland
  • RHAMM

ASJC Scopus subject areas

  • Molecular Biology

Cite this

Tolg, C., Yuan, H., Flynn, S. M., Basu, K., Ma, J., Tse, K. C. K., ... Turley, E. A. (Accepted/In press). Hyaluronan modulates growth factor induced mammary gland branching in a size dependent manner. Matrix Biology. https://doi.org/10.1016/j.matbio.2017.02.003

Hyaluronan modulates growth factor induced mammary gland branching in a size dependent manner. / Tolg, Cornelia; Yuan, Han; Flynn, Sarah M.; Basu, Kaustuv; Ma, Jenny; Tse, Kenneth Chor Kin; Kowalska, Beatrice; Vulkanesku, Diana; Cowman, Mary; McCarthy, James B.; Turley, Eva A.

In: Matrix Biology, 25.10.2016.

Research output: Contribution to journalArticle

Tolg, C, Yuan, H, Flynn, SM, Basu, K, Ma, J, Tse, KCK, Kowalska, B, Vulkanesku, D, Cowman, M, McCarthy, JB & Turley, EA 2016, 'Hyaluronan modulates growth factor induced mammary gland branching in a size dependent manner', Matrix Biology. https://doi.org/10.1016/j.matbio.2017.02.003
Tolg, Cornelia ; Yuan, Han ; Flynn, Sarah M. ; Basu, Kaustuv ; Ma, Jenny ; Tse, Kenneth Chor Kin ; Kowalska, Beatrice ; Vulkanesku, Diana ; Cowman, Mary ; McCarthy, James B. ; Turley, Eva A. / Hyaluronan modulates growth factor induced mammary gland branching in a size dependent manner. In: Matrix Biology. 2016.
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abstract = "Mammary gland morphogenesis begins during fetal development but expansion of the mammary tree occurs postnatally in response to hormones, growth factors and extracellular matrix. Hyaluronan (HA) is an extracellular matrix polysaccharide that has been shown to modulate growth factor-induced branching in culture. Neither the physiological relevance of HA to mammary gland morphogenesis nor the role that HA receptors play in these responses are currently well understood. We show that HA synthase (HAS2) is expressed in both ductal epithelia and stromal cells but HA primarily accumulates in the stroma. HA accumulation and expression of the HA receptors CD44 and RHAMM are highest during gestation when gland remodeling, lateral branch infilling and lobulo-alveoli formation is active. Molecular weight analyses show that approximately 98{\%} of HA at all stages of morphogenesis is >. 300. kDa. Low levels of 7-114. kDa HA fragments are also detected and in particular the accumulation of 7-21. kDa HA fragments are significantly higher during gestation than other morphogenetic stages (p <. 0.05). Using these in vivo results as a guide, in culture analyses of mammary epithelial cell lines (EpH4 and NMuMG) were performed to determine the roles of high molecular weight, 7-21. kDa (10. kDa MWavg) and HA receptors in EGF-induced branching morphogenesis. Results of these assays show that while HA synthesis is required for branching and 10. kDa HA fragments strongly stimulate branching, the activity of HA decreases with increasing molecular weight and 500. kDa HA strongly inhibits this morphogenetic process. The response to 10. kDa HA requires RHAMM function and genetic deletion of RHAMM transiently blunts lateral branching in vivo. Collectively, these results reveal distinct roles for HA polymer size in modulating growth factor induced mammary gland branching and implicates these polymers in both the expansion and sculpting of the mammary tree during gestation.",
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