Spermidine promotes human hair growth and is a novel modulator of human epithelial stem cell functions

TY - JOUR

T1 - Spermidine promotes human hair growth and is a novel modulator of human epithelial stem cell functions

AU - Ramot, Yuval

AU - Tiede, Stephan

AU - Bíró, Tamás

AU - Abu Bakar, Mohd Hilmi

AU - Sugawara, Koji

AU - Philpott, Michael P

AU - Harrison, Wesley

AU - Pietilä, Marko

AU - Paus, Ralf

PY - 2011

Y1 - 2011

N2 - BACKGROUND: Rapidly regenerating tissues need sufficient polyamine synthesis. Since the hair follicle (HF) is a highly proliferative mini-organ, polyamines may also be important for normal hair growth. However, the role of polyamines in human HF biology and their effect on HF epithelial stem cells in situ remains largely unknown.METHODS AND FINDINGS: We have studied the effects of the prototypic polyamine, spermidine (0.1-1 µM), on human scalp HFs and human HF epithelial stem cells in serum-free organ culture. Under these conditions, spermidine promoted hair shaft elongation and prolonged hair growth (anagen). Spermidine also upregulated expression of the epithelial stem cell-associated keratins K15 and K19, and dose-dependently modulated K15 promoter activity in situ and the colony forming efficiency, proliferation and K15 expression of isolated human K15-GFP+ cells in vitro. Inhibiting the rate-limiting enzyme of polyamine synthesis, ornithine decarboyxlase (ODC), downregulated intrafollicular K15 expression. In primary human epidermal keratinocytes, spermidine slightly promoted entry into the S/G2-M phases of the cell cycle. By microarray analysis of human HF mRNA extracts, spermidine upregulated several key target genes implicated e.g. in the control of cell adherence and migration (POP3), or endoplasmic reticulum and mitochondrial functions (SYVN1, NACA and SLC25A3). Excess spermidine may restrict further intrafollicular polyamine synthesis by inhibiting ODC gene and protein expression in the HF's companion layer in situ.CONCLUSIONS: These physiologically and clinically relevant data provide the first direct evidence that spermidine is a potent stimulator of human hair growth and a previously unknown modulator of human epithelial stem cell biology.

AB - BACKGROUND: Rapidly regenerating tissues need sufficient polyamine synthesis. Since the hair follicle (HF) is a highly proliferative mini-organ, polyamines may also be important for normal hair growth. However, the role of polyamines in human HF biology and their effect on HF epithelial stem cells in situ remains largely unknown.METHODS AND FINDINGS: We have studied the effects of the prototypic polyamine, spermidine (0.1-1 µM), on human scalp HFs and human HF epithelial stem cells in serum-free organ culture. Under these conditions, spermidine promoted hair shaft elongation and prolonged hair growth (anagen). Spermidine also upregulated expression of the epithelial stem cell-associated keratins K15 and K19, and dose-dependently modulated K15 promoter activity in situ and the colony forming efficiency, proliferation and K15 expression of isolated human K15-GFP+ cells in vitro. Inhibiting the rate-limiting enzyme of polyamine synthesis, ornithine decarboyxlase (ODC), downregulated intrafollicular K15 expression. In primary human epidermal keratinocytes, spermidine slightly promoted entry into the S/G2-M phases of the cell cycle. By microarray analysis of human HF mRNA extracts, spermidine upregulated several key target genes implicated e.g. in the control of cell adherence and migration (POP3), or endoplasmic reticulum and mitochondrial functions (SYVN1, NACA and SLC25A3). Excess spermidine may restrict further intrafollicular polyamine synthesis by inhibiting ODC gene and protein expression in the HF's companion layer in situ.CONCLUSIONS: These physiologically and clinically relevant data provide the first direct evidence that spermidine is a potent stimulator of human hair growth and a previously unknown modulator of human epithelial stem cell biology.

KW - Cell Proliferation

KW - Cell Separation

KW - Colony-Forming Units Assay

KW - Epidermis

KW - Epithelial Cells

KW - Female

KW - Gene Expression Profiling

KW - Green Fluorescent Proteins

KW - Hair

KW - Hair Follicle

KW - Humans

KW - Keratinocytes

KW - Keratins

KW - Ornithine Decarboxylase

KW - Promoter Regions, Genetic

KW - Spermidine

KW - Stem Cells

KW - Up-Regulation

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1371/journal.pone.0022564

DO - 10.1371/journal.pone.0022564

M3 - SCORING: Journal article

C2 - 21818338

VL - 6

SP - e22564

JO - PLOS ONE

JF - PLOS ONE

SN - 1932-6203

IS - 7

ER -