Inositol kinase and its product accelerate wound healing by modulating calcium levels, Rho GTPases, and F-actin assembly

Soto, Ximena; Li, Jingjing; Lea, Robert; Dubaissi, Eamon; Papalopulu, Nancy; Amaya, Enrique

doi:10.1073/pnas.1217308110

Cited by 37 publications

(50 citation statements)

References 36 publications

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“…This could be due to the dependence on Ca 2+ dynamics for the proliferation of cell precursors of all regenerating tissues in the tail. Indeed, skin repair after wound healing in Xenopus embryos and skin homeostasis in human cells and mice depend on Ca 2+ stores for the enhancement of skin cell proliferation [37, 38]. Similarly, neural cell precursor proliferation is regulated by Ca 2+ dynamics [21, 35, 36].…”

Section: Discussionmentioning

confidence: 99%

Spontaneous calcium transients manifest in the regenerating muscle and are necessary for skeletal muscle replenishment

Borodinsky

2014

Cell Calcium

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Summary Tissue regeneration entails replenishing of damaged cells, appropriate cell differentiation and inclusion of regenerated cells into functioning tissues. In adult humans, the capacity of the injured spinal cord and muscle to self-repair is limited. In contrast, the amphibian larva can regenerate its tail after amputation with complete recovery of muscle, notochord and spinal cord. The cellular and molecular mechanisms underlying this phenomenon are still unclear. Here we show that upon injury muscle cell precursors exhibit Ca2+ transients that depend on Ca2+ release from ryanodine receptor-operated stores. Blockade of these transients impairs muscle regeneration. Furthermore, inhibiting Ca2+ transients in the regenerating tail prevents the activation and proliferation of muscle satellite cells, which results in deficient muscle replenishment. These findings suggest that Ca2+-mediated activity is critical for the early stages of muscle regeneration, which may lead to developing effective therapies for tissue repair.

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Section: Discussionmentioning

confidence: 99%

Spontaneous calcium transients manifest in the regenerating muscle and are necessary for skeletal muscle replenishment

Borodinsky

2014

Cell Calcium

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“…TRH binding to a TRH GPCR isoform would trigger a signalling cascade involving phospholipase C, an increase in downstream inositol 1,4,5-trisphosphate (InsP 3 ) production and activation of protein kinase C. Intriguingly, a recent report using Xenopus embryonic wound healing assays has shown that both InsP 3 and its metabolite, inositol 1,3,4,5-tetrakisphosphate (InsP 4 ), are able to accelerate the speed of wound healing [72]. Further signalling events triggered by TRH binding can involve PKC-dependent or independent activation of mitogen-activated protein kinase (MAPK).…”

Section: Discussionmentioning

confidence: 99%

Thyrotropin-Releasing Hormone (TRH) Promotes Wound Re-Epithelialisation in Frog and Human Skin

et al. 2013

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There remains a critical need for new therapeutics that promote wound healing in patients suffering from chronic skin wounds. This is, in part, due to a shortage of simple, physiologically and clinically relevant test systems for investigating candidate agents. The skin of amphibians possesses a remarkable regenerative capacity, which remains insufficiently explored for clinical purposes. Combining comparative biology with a translational medicine approach, we report the development and application of a simple ex vivo frog (Xenopus tropicalis) skin organ culture system that permits exploration of the effects of amphibian skin-derived agents on re-epithelialisation in both frog and human skin. Using this amphibian model, we identify thyrotropin-releasing hormone (TRH) as a novel stimulant of epidermal regeneration. Moving to a complementary human ex vivo wounded skin assay, we demonstrate that the effects of TRH are conserved across the amphibian-mammalian divide: TRH stimulates wound closure and formation of neo-epidermis in organ-cultured human skin, accompanied by increased keratinocyte proliferation and wound healing-associated differentiation (cytokeratin 6 expression). Thus, TRH represents a novel, clinically relevant neuroendocrine wound repair promoter that deserves further exploration. These complementary frog and human skin ex vivo assays encourage a comparative biology approach in future wound healing research so as to facilitate the rapid identification and preclinical testing of novel, evolutionarily conserved, and clinically relevant wound healing promoters.

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“…We developed an active Rho GTPase GST pull-down assay applicable to our in vivo embryonic wound-healing system, to detect the levels of active Rac, Rho and Cdc42 (supplementary material Fig. S7) (Soto et al, 2013). The binding domain of PAK1 (aa 70-117) was used for pulling down active Rac and Cdc42 (Zhang et al, 1998), and the binding domain of Rhotekin for active Rho (Benink and Bement, 2005).…”

Section: Erk and Pi3k Signalling Regulate Cytoskeleton Organisation Tmentioning

confidence: 99%

ERK and phosphoinositide 3-kinase temporally coordinate different modes of actin-based motility during embryonic wound healing

Li¹,

Zhang²,

Soto³

et al. 2013

Development

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SummaryEmbryonic wound healing provides a perfect example of efficient recovery of tissue integrity and homeostasis, which is vital for survival. Tissue movement in embryonic wound healing requires two functionally distinct actin structures: a contractile actomyosin cable and actin protrusions at the leading edge. Here, we report that the discrete formation and function of these two structures is achieved by the temporal segregation of two intracellular upstream signals and distinct downstream targets. The sequential activation of ERK and phosphoinositide 3-kinase (PI3K) signalling divides Xenopus embryonic wound healing into two phases. In the first phase, activated ERK suppresses PI3K activity, and is responsible for the activation of Rho and myosin-2, which drives actomyosin cable formation and constriction. The second phase is dominated by restored PI3K signalling, which enhances Rac and Cdc42 activity, leading to the formation of actin protrusions that drive migration and zippering. These findings reveal a new mechanism for coordinating different modes of actin-based motility in a complex tissue setting, namely embryonic wound healing.

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Inositol kinase and its product accelerate wound healing by modulating calcium levels, Rho GTPases, and F-actin assembly

Cited by 37 publications

References 36 publications

Spontaneous calcium transients manifest in the regenerating muscle and are necessary for skeletal muscle replenishment

Spontaneous calcium transients manifest in the regenerating muscle and are necessary for skeletal muscle replenishment

Thyrotropin-Releasing Hormone (TRH) Promotes Wound Re-Epithelialisation in Frog and Human Skin

ERK and phosphoinositide 3-kinase temporally coordinate different modes of actin-based motility during embryonic wound healing

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