Context-dependent effect of sPLA 2 -IIA induced proliferation on murine hair follicle stem cells and human epithelial cancer

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Abstract

Background

Tissue stem cells (SCs) and cancer cells proliferation is regulated by many common signalling mechanisms. These mechanisms temporally balance proliferation and differentiation events during normal tissue homeostasis and repair. However, the effect of these aberrant signalling mechanisms on the ultimate fate of SCs and cancer cells remains obscure.

Methods

To evaluate the functional effects of Secretory Phospholipase A ₂-IIA (sPLA ₂-IIA) induced abnormal signalling on normal SCs and cancer cells, we have used K14-sPLA ₂-IIA transgenic mice hair follicle stem cells (HFSCs), DMBA/TPA induced mouse skin tumour tissues, human oral squamous cell carcinoma (OSCC) and skin squamous cell carcinoma (SCC) derived cell lines.

Findings

Our study demonstrates that sPLA ₂-IIA induces rapid proliferation of HFSCs, thereby altering the proliferation dynamics leading to a complete loss of the slow cycling H2BGFP positive HFSCs. Interestingly, in vivo reversion study by JNK inhibition exhibited a significant delay in post depilation hair growth, confirming that sPLA ₂-IIA promotes HFSCs proliferation through JNK/c-Jun signalling. In a different cellular context, we showed increased expression of sPLA ₂-IIA in human OSCC and mouse skin cancer tissues. Importantly, a xenograft of sPLA ₂-IIA knockdown cells of OSCC and SCC cell lines showed a concomitant reduction of tumour volume in NOD-SCID mice and decreased JNK/c-Jun signalling.

Interpretation

This study unravels how an increased proliferation induced by a common proliferation inducer (sPLA ₂-IIA) alters the fate of normal SCs and cancer cells distinctively through common JNK/c-Jun signalling. Thus, sPLA ₂-IIA can be a potential target for various diseases including cancer.

Fund

This work was partly supported by the Indian Council of Medical Research (ICMR-3097) and ACTREC (42) grants.

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Most cited references 49

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Coexistence of quiescent and active adult stem cells in mammals.

Linheng Li, Hans Clevers (2010)

Adult stem cells are crucial for physiological tissue renewal and regeneration after injury. Prevailing models assume the existence of a single quiescent population of stem cells residing in a specialized niche of a given tissue. Emerging evidence indicates that both quiescent (out of cell cycle and in a lower metabolic state) and active (in cell cycle and not able to retain DNA labels) stem cell subpopulations may coexist in several tissues, in separate yet adjoining locations. Here, we summarize these findings and propose that quiescent and active stem cell populations have separate but cooperative functional roles.

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Dynamics between stem cells, niche, and progeny in the hair follicle.

Ya-Chieh Hsu, H Amalia Pasolli, Elaine Fuchs (2011)

Here, we exploit the hair follicle to define the point at which stem cells (SCs) become irreversibly committed along a differentiation lineage. Employing histone and nucleotide double-pulse-chase and lineage tracing, we show that the early SC descendents en route to becoming transit-amplifying cells retain stemness and slow-cycling properties and home back to the bulge niche when hair growth stops. These become the primary SCs for the next hair cycle, whereas initial bulge SCs become reserves for injury. Proliferating descendents further en route irreversibly lose their stemness, although they retain many SC markers and survive, unlike their transit-amplifying progeny. Remarkably, these progeny also home back to the bulge. Combining purification and gene expression analysis with differential ablation and functional experiments, we define critical functions for these non-SC niche residents and unveil the intriguing concept that an irreversibly committed cell in an SC lineage can become an essential contributor to the niche microenvironment. Copyright Â© 2011 Elsevier Inc. All rights reserved.

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Defining Hematopoietic Stem and Progenitor Cell Turnover by Analysis of Histone 2B-GFP Dilution

Adlen Foudi, Konrad Hochedlinger, Denille Van Buren … (2008)

Hematopoietic stem cells (HSCs) are thought to divide infrequently based on their resistance to cytotoxic injury targeted at rapidly cycling cells1, 2 and have been presumed to retain labels such as the nucleotide analogue 5-bromodeoxyuridine (BrdU). However, recently it has been demonstrated that BrdU-retention is neither sensitive nor specific for HSCs3. Here we show that transient, transgenic expression of a Histone2B (H2B)-Green Fluorescent Protein (GFP) fusion protein in mice allows superior labeling of HSCs and permits improved analysis of their turnover in combination with other markers. Mathematical modeling of H2B-GFP dilution in HSCs, identified with a highly stringent marker combination (L−K+S+CD48−CD150+)4, revealed unexpected heterogeneity in their proliferation rates and suggests that ~ 20% of HSCs turn over at an extremely low rate (≤ 0.8–1.8% per day). Prospective isolation and transplantation of L−K+S+CD48−CD150+ HSCs with different H2B-GFP levels revealed that higher H2B-GFP label retention correlates with superior long-term repopulation potential.

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Author and article information

Contributors

Sanjeev K. Waghmare

Journal

Journal ID (nlm-ta): EBioMedicine

Journal ID (iso-abbrev): EBioMedicine

Title: EBioMedicine

Publisher: Elsevier

ISSN (Electronic): 2352-3964

Publication date PMC-release: 11 September 2019

Publication date Collection: October 2019

Publication date (Electronic): 11 September 2019

Volume: 48

Pages: 364-376

Affiliations

[a ]Stem Cell Biology Group, Waghmare Lab, Cancer Research Institute, Advanced Centre for Treatment Research and Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai 410210, Maharashtra, India

[b ]Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai 400085, India

Author notes

[* ]Corresponding author. swaghmare@ 123456actrec.gov.in

[1]

The authors have contributed equally as first author.

[2]

The authors have contributed equally as second author.

Article

Publisher ID: S2352-3964(19)30576-6

DOI: 10.1016/j.ebiom.2019.08.053

PMC ID: 6838435

PubMed ID: 31521610

SO-VID: 09e8cdee-1cf7-439f-9d5f-acac0f08a18b

License:

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

History

Date received : 31 July 2018

Date revision received : 23 August 2019

Date accepted : 23 August 2019

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