Substance P enhances the local activation of NK 1 R-expressing c-kit +  cardiac progenitor cells in right atrium of ischemia/reperfusion-injured heart

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Abstract

Background

Localization of neurokinin 1 receptor (NK ₁R), the endogenous receptor for neuropeptide substance P (SP), has already been described for the right atrium (RA) of the heart. However, the biological role of SP/NK ₁R signal pathways in the RA remains unclear.

Sprague-Dawley rats were randomly divided into 4 groups ( n = 22 each); subjected to sham, ischemia/reperfusion-injury (I/R), I/R with 5 nmole/kg SP injection (SP + I/R), and SP + I/R with 1 mg/kg RP67580 injection (RP, a selective non-peptide tachykinin NK ₁R antagonist) (RP/SP + I/R). The left anterior descending coronary artery was occluded for 40 min followed by 1 day reperfusion with SP or SP + RP or without either. After 1 day, both atria and ventricles as well as the heart apexes were collected.

Results

SP promoted the expression of c-Kit, GATA4, Oct4, Nanog, and Sox2 in only the RA of the SP + I/R rats via NK ₁R activation. In agreement with these observations, NK ₁R-expressing c-Kit ⁺ Nkx2.5 ⁺GATA4 ⁺ cardiac progenitor cells (CPCs) in the ex vivo RA explant outgrowth assay markedly migrated out from RA ^{1 day SP + I/R} approximately 2-fold increase more than RA ^{1 day I/R}. Treatment of SP promoted proliferation, migration, cardiosphere formation, and potential to differentiate into cardiomyocytes. Using RP inhibitor, NK ₁R antagonist not only inhibited cell proliferation and migration but also reduced the formation of cardiosphere and differentiation of c-Kit ⁺ CPCs.

Conclusion

SP/NK ₁R might play a role as a key mediator involved in the cellular response to c-Kit ⁺ CPC expansion in RA of the heart within 24 h after I/R.

Related collections

Most cited references 24

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A new role of substance P as an injury-inducible messenger for mobilization of CD29(+) stromal-like cells.

T. J. Kim, Young Kwon, Bong W Ahn … (2009)

Tissue injury may create a specific microenvironment for inducing the systemic participation of stromal-like cells in the repair process. Here we show that substance P is an injury-inducible factor that acts early in the wound healing process to induce CD29(+) stromal-like cell mobilization. Likewise, mobilization of such cells also occurs in uninjured mice, rats and rabbits if substance P is intravenously injected. Upon further characterization these substance P-mobilized CD29(+) cells were found to be similar to stromal cells from a number of connective tissues, including bone marrow (that is, bone marrow stromal cells, or BMSCs). Both substance P injection and transfusion of autologously derived substance P-mobilized CD29(+) cells from uninjured rabbits accelerated wound healing in an alkali burn model. Also, epithelial engraftment of the transfused cells into the injured tissue occurred during the wound healing. Finally, using human BMSCs as a test population, we show that substance P stimulates transmigration, cell proliferation, activation of the extracellular signal-related kinases (Erk) 1 and 2 and nuclear translocation of beta-catenin in vitro. This finding highlights a previously undescribed function of substance P as a systemically acting messenger of injury and a mobilizer of CD29(+) stromal-like cells to participate in wound healing.

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Role for substance p-based nociceptive signaling in progenitor cell activation and angiogenesis during ischemia in mice and in human subjects.

Silvia Amadesi, Carlotta Reni, Rajesh Katare … (2012)

Pain triggers a homeostatic alarm reaction to injury. It remains unknown, however, whether nociceptive signaling activated by ischemia is relevant for progenitor cells (PC) release from bone marrow. To this end, we investigated the role of the neuropeptide substance P (SP) and cognate neurokinin 1 (NK1) nociceptor in PC activation and angiogenesis during ischemia in mice and in human subjects. The mouse bone marrow contains sensory fibers and PC that express SP. Moreover, SP-induced migration provides enrichment for PC that express NK1 and promote reparative angiogenesis after transplantation in a mouse model of limb ischemia. Acute myocardial infarction and limb ischemia increase SP levels in peripheral blood, decrease SP levels in bone marrow, and stimulate the mobilization of NK1-expressing PC, with these effects being abrogated by systemic administration of the opioid receptor agonist morphine. Moreover, bone marrow reconstitution with NK1-knockout cells results in depressed PC mobilization, delayed blood flow recovery, and reduced neovascularization after ischemia. We next asked whether SP is instrumental to PC mobilization and homing in patients with ischemia. Human PC express NK1, and SP-induced migration provides enrichment for proangiogenic PC. Patients with acute myocardial infarction show high circulating levels of SP and NK1-positive cells that coexpress PC antigens, such as CD34, KDR, and CXCR4. Moreover, NK1-expressing PC are abundant in infarcted hearts but not in hearts that developed an infarct after transplantation. Our data highlight the role of SP in reparative neovascularization. Nociceptive signaling may represent a novel target of regenerative medicine.

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Characterization of long-term cultured c-kit+ cardiac stem cells derived from adult rat hearts.

Toshiharu Shin'oka, Nanako Kawaguchi, S Miyamoto … (2009)

Previous studies have revealed c-kit-positive (c-kit(+)) cardiac stem cells (CSCs) in the adult mammalian heart and these cells could be a suitable cell source for heart regeneration therapy. However, these cells have not been fully evaluated in terms of characterization and effect of long-term culture, which is necessary for their safe and optimal usage. Therefore, we isolated c-kit(+) CSCs from adult rat hearts to characterize these cells and investigate stability over long-term culture. We performed isolations of c-kit(+) CSCs 11 times and passaged them 40 times in a bulk culture system; we termed these cultures, bulk culture CSCs (CSC-BC). c-kit(+) CSCs expressed stemness genes and exhibited stem cell properties of single cell-derived clone formation, cardiosphere generation, and potential to differentiate into the three main cardiac lineages: cardiomyocyte, smooth muscle, and endothelial cells in vitro. Over long-term culture, some CSC-BC up-regulated GATA-4 expression, which resulted in enhanced cardiomyocyte differentiation, suggesting that the GATA-4 high c-kit(+) CSCs have potent cardiac regenerative potential. We also observed the spontaneous differentiation into cells other than cardiac lineages, such as adipocyte and skeletal myocyte. This effect of long-term culture on the c-kit(+) CSCs has not been previously reported. Interestingly, when c-kit(+) CSCs were co-cultured with adult rat cardiomyocytes, we found increased cardiomyocyte survival, and the growth factors, insulin-like growth factor 1 (IGF-1) and vascular endothelial growth factor (VEGF), appeared to be responsible factors. The present study suggests that c-kit(+) CSCs have great therapeutic potential yet should be further investigated and optimized as a cell source for regenerative therapies prior to transplantation.

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Author and article information

Contributors

Weon Kim: mylovekw@hanmail.net

Journal

Journal ID (nlm-ta): BMC Mol Cell Biol

Journal ID (iso-abbrev): BMC Mol Cell Biol

Title: BMC Molecular and Cell Biology

Publisher: BioMed Central (London )

ISSN (Electronic): 2661-8850

Publication date (Electronic): 9 June 2020

Publication date PMC-release: 9 June 2020

Publication date Collection: 2020

Volume: 21

Electronic Location Identifier: 41

Affiliations

[1 ]Division of Cardiology, Department of Internal Medicine, Kyung Hee University Hospital, Kyung Hee University, Hoegi-dong, Dongdaemun-gu, Seoul, 130-701 Republic of Korea

[2 ]GRID grid.440951.d, ISNI 0000 0004 0371 9862, Department of Mechanical Engineering, , Korea Polytechnic University, ; 237 Sangidaehak Street, Si-heung City, Republic of Korea

[3 ]GRID grid.459480.4, ISNI 0000 0004 1758 0638, The Department of Cardiology, , Yanbian University Hospital, ; Yanji, China

Article

Publisher ID: 286

DOI: 10.1186/s12860-020-00286-x

PMC ID: 7285458

PubMed ID: 32517655

SO-VID: 8fe2b7c1-c0ff-4523-9d29-72526adb1975

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 19 August 2019

Date accepted : 1 June 2020

Funding

Funded by: National Research Foundation (KR)

Award ID: 2016R1A6A3A11933448

Award ID: 2017R1A6A03015562

Award ID: 2018R1A2B6009316

Award Recipient : Weon Kim

Custom metadata

Keywords: substance p,ischemia-reperfusion,c-kit+ cardiac progenitor cells,neurokinin 1 receptor, right atrium

Data availability:

Keywords: substance p, ischemia-reperfusion, c-kit+ cardiac progenitor cells, neurokinin 1 receptor, right atrium