Elsevier

Surgery

Volume 142, Issue 2, August 2007, Pages 215-221
Surgery

Society of University Surgeon
In the adult mesenchymal stem cell population, source gender is a biologically relevant aspect of protective power

https://doi.org/10.1016/j.surg.2007.04.013Get rights and content

Background

Acute treatment with bone marrow mesenchymal stem cells (MSC) reduces myocardial infarct size by multiple mechanisms, including the paracrine release of protective growth factors. Female MSCs produce more growth factor when stressed; therefore, we hypothesized that myocardial protection provoked by female MSCs would be greater than that elicited by male MSCs.

Methods

Hearts were subjected to 25 min of warm global ischemia, 40 min of reperfusion, and randomly assigned into one of three groups: (1) vehicle treated; (2) male MSC treated; and (3) female MSC treated. Myocardial function was continuously recorded and in separate experiments, male and female MSC growth factor production was assessed by ELISA.

Results

All indices of functional recovery were significantly higher in the stem cell infused rat heart compared with control hearts. Interestingly, female MSC treated rat hearts demonstrated significantly greater recovery of left ventricular developed pressure, +dP/dT, and −dP/dT than male MSC treated hearts at end reperfusion. In addition, male MSCs produced significantly greater tumor necrosis factor alpha, and significantly less vascular endothelial growth factor than female MSCs.

Conclusions

This study is the first to demonstrate that, in the adult mesenchymal population, source gender is a biologically relevant aspect of ultimate stem cell function in the heart.

Introduction

Modern surgical and medical therapies have proven largely inadequate in the prevention and treatment of heart failure. Recently, considerable interest has focused instead on cell-based cardiac repair, with particular emphasis on stem cells to replace or reverse the loss of myocardial contractile cells.1 Stem cells may mediate their beneficial cardiac effects in part by paracrine mechanisms.2, 3 Paracrine-mediated actions have proven to potentiate positive myocardial remodeling, improved function, reduced apoptosis, and decreased infarct size.4 Indeed, we have previously demonstrated that bone marrow stem cell (BMSC) differentiation is not required for cardioprotection; acute application of human BMSC into myocardium subjected to ischemia reperfusion improved functional recovery, decreased proinflammatory cytokine production, and decreased activation of proapoptotic caspases.5

This paracrine protection may be enhanced by ex vivo modification. Pro-survival Akt genetic modification, vascular endothelial growth factor-A (VEGF) transduction,6 and even preconditioning7, 8, 9 have shown to enhance stem cell paracrine cardioprotection in animal models. Interestingly, we have recently shown that gender identification may also allow enhanced protective growth factor production. When exposed to LPS or hypoxia, female stem cells demonstrate increased release of VEGF and decreased production of inflammatory tumor necrosis factor alpha (TNF)-α in comparison to males.2, 10 Similar to gender differences in stem cell activation, several recent studies have shown that gender differences exist in monocyte proinflammatory cytokine production.11, 12, 13 However, no study has addressed whether gender differences in stem cell growth factor production are biologically relevant, causing subsequent gender differences in stem cell paracrine myocardial protection.

Among the many sources of adult stem cells, BMSCs have shown particular promise. Within this population, hematopoietic stem cells (HSCs) and nonhematopoietic mesenchymal stem cells (MSCs) have each demonstrated positive remodeling and regeneration of viable tissues.1 However, MSCs have advantages over the well-characterized HSC population, including availability from small aspirates of donor bone marrow, ease of expansion in an in vitro cell culture, simple isolation via plastic adherence, and an innate ability to evade rejection.14 We hypothesize that murine MSCs are acutely cardioprotective against ischemia reperfusion injury (I/R) in the isolated perfused rat heart and that female gender in stem cells enhances MSC activation and MSC cardioprotection.

Section snippets

Animals

Normal male and female strain C57BL/6J mice (The Jackson Laboratory, Bar Harbor, Me.) and normal (280-300 g, 9-10 wk) Sprague-Dawley rats (Harlan, Indianapolis, Ind.) were fed a standard diet and acclimated in a quiet quarantine room for 1 wk before the experiments. The animal protocol was reviewed and approved by the Indiana Animal Care and Use Committee of Indiana University. All animals received humane care in compliance with the “Guide for the Care and Use of Laboratory Animals” (NIH

Myocardial function

Ischemia/reperfusion resulted in markedly decreased left ventricular developed pressure (LVDP) in all groups. Postischemic recovery of LVDP (expressed as percentage of preischemic function) was significantly higher (P < 0.05) in hearts with MSCs (56.6 ± 5.9%) than control hearts (35.7 ± 3.5%) (Fig 1). However, female MSC conferred significantly greater protection (P < 0.05) of LVDP (67.1 ± 8.5%) compared with male MSC infusion (46.2 ± 4.1%) (Fig 2).

Left ventricular end diastolic pressure (EDP)

Discussion

The results of this study are the first demonstration that (1) both male and female murine mesenchymal stem cells improve functional recovery after ischemia; and (2) female murine mesenchymal stem cells confer greater protection of myocardial function after ischemia compared to male mesenchymal stem cells, possibly because of increased VEGF and decreased TNF-α release during hypoxia.

Stem cell therapy is a promising treatment modality for injured cardiac tissue. However, we now appreciate that

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    Supported in part by NIH R01GM070628 (DRM), NIH NRSA F32HL085982 (TAM/DRM), and AHA Post-doctoral Fellowship 0526008Z (MW/DRM). This investigation was conducted in a facility constructed with support from Research Facilities Improvement Program Grant Number C06 RR015481-01 from the National Center for Research Resources, National Institutes of Health.

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