• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
J Mol Cell Cardiol. Author manuscript; available in PMC Jan 1, 2008.
Published in final edited form as:
PMCID: PMC1779905
NIHMSID: NIHMS16043

GENDER DIFFERENCES IN INJURY INDUCED MESENCHYMAL STEM CELL APOPTOSIS, EXPRESSION OF VEGF, TNF, AND IL-6 AND ABROGATION VIA TNFR1 ABLATION

Abstract

Concomitant pro- and anti-inflammatory properties of bone marrow stem cells (BMSC) may be an important aspect of their ability to heal injured tissue. However, very few studies have examined whether gender differences exist in BMSC function. Indeed, it remains unknown whether gender differences exist in BMSC function and ability to resist apoptosis, and if so, whether TNF receptor 1 (TNFR1) plays a role in these differences. We hypothesized that TNFR1 ablation equalizes gender differences in bone marrow mesenchymal stem cell (MSC) apoptosis, as well as expression of vascular endothelial growth factor (VEGF), TNF, and interleukin (IL)-6. Mouse MSCs from male wildtype (WT), female WT, male TNFR1 knockouts (TNFR1KO), and female TNFR1KO were stressed by endotoxin 200 ng/ml or 1 hr hypoxia. MSC activation was determined by measuring VEGF, TNF, and IL-6 production (ELISA). Differences considered significant if p<0.05. LPS and hypoxia resulted in significant activation in all experimental groups compared to controls. Male WT demonstrated significantly greater TNF and IL-6 and significantly less VEGF release than female WT MSCs. However, release of TNF, IL-6, and VEGF in male TNFR1 knockouts differed from male WT, but was not different from female WT MSCs. Similarly apoptosis in hypoxic male TNFRIKO differed from male WT, but it was not different from apoptosis from WT female. Female WT did not differ in TNF, IL-6, and VEGF release compared to female TNFR1KO. Gender differences exist in injury induced BMSC VEGF, TNF, and IL-6 expression. TNFR1 may autoregulate VEGF, TNF, and IL-6 expression in males more than females. MSCs are novel therapeutic agents for organ protection, but further study of the disparate expression of VEGF, TNF, and IL-6 in males and females as well as the role of TNFR1 in these gender differences is necessary to maximize this protection.

Keywords: mesenchymal stem cell, protection, endotoxin, sex, hypoxia, apoptosis

INTRODUCTION

Bone marrow stem cells (BMSCs) represent a novel treatment modality with increasing therapeutic potential [1, 2]. Bone marrow hematopoietic stem cells (HSCs) [3] and nonhematopoietic mesenchymal stem cells (MSCs) [4] have each demonstrated positive remodeling and regeneration of viable tissues. However, recent experimental studies questioning the engraftment and transdifferentiation of BMSCs [5], HSCs [6], and MSCs [7] suggests that stem cells mediate their beneficial effects via complex paracrine actions. Indeed, we and others have previously demonstrated that 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 [8, 9]. Thus, concomitant pro- and anti-inflammatory properties of BMSCs may be an important aspect of their ability to heal injured tissue. Several recent studies have shown that gender differences exist in monocyte proinflammatory cytokine production [1012]. No study has addressed gender differences in the pro- and anti- inflammatory properties of BMSCs.

Proinflammatory tumor necrosis factor-alpha (TNF) is induced in response to various injuries [13] and plays a central role in post-injured organ dysfunction, local tissue cell apoptosis, as well as induction of proinflammatory signaling [14]. It is now recognized that TNF acts by binding to a 55-kDa receptor (TNFR1) and/or a 75-kDa receptor (TNFR2). Although these two receptors induce both distinct and overlapping responses, dysfunction and apoptosis in various tissues are initiated by binding to TNFR1 [15]. We and others have shown significantly improved myocardial function in TNFR1 knockout mice compared to wild type mice after myocardial infarction [16]. Further, the female advantage after myocardial infarction may be associated with their resistance to myocardial TNFR1 signaling [16]. Although TNFR1 exists in BMSCs [17], no study has addressed the role of TNFR1 and gender on bone marrow stem cell activation and function.

MSCs are a relatively underexplored population of BMSCs that may have advantages over the well characterized HSC population [18, 19]. We hypothesized that TNFR1 ablation equalizes gender differences in bone marrow mesenchymal stem cell expression of VEGF, TNF, and IL-6. The purposes of this study were to investigate the effect of endotoxin (lipopolysaccharide (LPS)) and hypoxia on wild type and TNFR1 knockout mouse bone marrow MSC activation as measured by: 1) vascular endothelial growth factor (VEGF) expression; 2) TNF expression; 3) interleukin (IL)-6 expression; and 4) MSC apoptosis.

METHODS

Animals

C57BL/6J wild type (WT) mice and mice with targeted deletion of TNFR1 (TNFR1KO) (The Jackson Laboratory, Bar Harbor, ME) of both genders were fed a standard diet and acclimated in a quiet quarantine room for one week 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 publication No. 85-23, revised 1985).

Preparation of Mouse Bone Marrow Stromal Cells

A single-step purification method using adhesion to cell culture plastic is employed as previously described[20] with the following modifications: Mouse bone marrow stromal cells were collected, after sacrifice of 8 week old mice, from bilateral femurs and tibias by removing the epiphyses and flushing the shaft with complete media (Iscove’s Modified Dulbecco’s Medium (GIBCO Invitrogen, Carlsbad, CA) and 10% fetal bovine serum (GIBCO Invitrogen, Carlsbad, CA)) using a syringe with a 23G needle. Cells were disaggregated by vigorous pipetting several times. Cells were passed through 30-μm nylon mesh to remove remaining clumps of tissue. Cells were washed by adding complete media, centrifuging for 5 min at 300 rpm @ 24°C and removing supernatant. The cell pellet was then resuspended and cultured in 75 cm2 culture flasks with complete media at 37°C. MSCs preferentially attached to the polystyrene surface; after 48 h, nonadherent cells in suspension were discarded. Fresh complete medium was added and replaced every three or four days thereafter. MSC cultures were maintained at 37°C in 5% CO2 in air. When the cultures reached 90% of confluence, the MSC culture was passaged; cells were recovered by the addition of a solution 0.25% trypsi-EDTA (GIBCO Invitrogen, Carlsbad, CA) and replated in 75 cm2 culture flasks.

Experimental groups

MSCs were plated in 12 well plates in a concentration of 1 x 106 cells / well / ml. MSCs were divided into four experimental groups: 1) male WT; 2) female WT; 3) male TNFR1KO; and 4) female TNFR1KO. MSCs (triplicate wells per group) were then stressed with LPS 200 ng/ml or 1 hr hypoxia. After 24 h incubation, supernatants were harvested for vascular endothelial growth factor-A (VEGF), TNF, and IL-6 assay (ELISA). The experiment was repeated on three separate occasions (n=6–11 wells / group).

TNF, IL-6, and VEGF ELISA

VEGF, TNF, and IL-6 release in the BMSC were determined by enzyme-linked immunosorbent assay (ELISA) using a commercially available ELISA set (R&D Systems Inc., Minneapolis, MN and BD Biosciences, San Diego, CA). ELISA was performed according to the manufacturer’s instructions. All samples and standards were measured in duplicate.

Apoptosis ELISA

Apoptosis in MSCs subjected to hypoxia was determined by ELISA using a commercially available Cell Death Detection ELISA set (Roche Applied Science, Indianapolis, IN). ELISA was performed according to the manufacturer’s instructions. All samples and standards were measured in duplicate.

Presentation of data and statistical analysis

All reported values are mean ± SEM. Data was compared using two-way analysis of variance (ANOVA) with post-hoc Bonferroni test or Student’s t-test. A two-tailed probability value of less than 0.05 was considered statistically significant.

RESULTS

Effect of LPS on MSC Activation

LPS resulted in significant activation of MSCs. LPS provoked significant TNF production in male WT (657.7 ± 55.2 pg /ml), female WT (184.8 ± 82.1 pg /ml), male TNFR1KO (599.9 ± 132.2 pg/ml), and female TNFR1KO (14.51 ± 3.1 pg/ml) in comparison to controls as shown in Figure 1. In addition, LPS induced significant VEGF release in male WT (889.8 ± 44.8 pg/ml), female WT (871.1 ± 83.4 pg/ml), male TNFR1KO (736.6 ± 66.8 pg/ml), and female TNFR1KO (762.5 ± 118.5 pg/ml) in comparison to controls as shown in Figure 2. Likewise, LPS provoked a significant increase of IL-6 in in male WT (157 fold), female WT (40 fold), male TNFR1KO (61 fold), and female TNFR1KO (40 fold) in comparison to controls as shown in Figure 3.

Figure 1
MSC WT activation (TNF release) after injury. A. Male and female WT after LPS exposure, results expressed as pg/ml, mean ± SEM, *p<0.05 vs control, +p<0.05 male vs female. B. Male and female TNFR1KO after LPS exposure, results ...
Figure 2
MSC WT activation (VEGF release) after injury. A. Male and female WT after LPS exposure, results expressed as pg/ml, mean ± SEM, *p<0.05 vs control, +p<0.05 male vs female. B. Male and female TNFR1KO after LPS exposure, results ...
Figure 3
MSC WT activation (IL-6 release) after injury. A. Male and female WT after LPS exposure, results expressed as pg/ml, mean ± SEM, *p<0.05 vs control, +p<0.05 male vs female. B. Male and female TNFR1KO after LPS exposure, results ...

Effect of hypoxia on MSC Activation

Hypoxia resulted in significant activation of MSCs. Hypoxia provoked significant TNF production in male WT (40.5 ± 5.2 pg /ml), female WT (11.6 ± 2.2 pg /ml), male TNFR1KO (16.1 ± 3.5 pg/ml), and female TNFR1KO (5.5 ± 1.6 pg/ml) in comparison to controls as shown in Figure 1. In addition, hypoxia induced significant VEGF release in male WT (716.2 ± 1.9 pg/ml), female WT (742.5 ± 5.5 pg/ml), male TNFR1KO (500.0 ± 11.5 pg/ml), and female TNFR1KO (634.9 ± 13.8 pg/ml) in comparison to controls as shown in Figure 2. Likewise, LPS provoked a significant increase of IL-6 in in male WT (9 fold), female WT (4 fold), male TNFR1KO (2 fold), and female TNFR1KO (3 fold) in comparison to controls as shown in Figure 3.

Gender differences in MSC Activation

However, both hypoxia and endotoxin demonstrated significantly greater TNF and IL-6 in WT male and significantly less VEGF expression than female WT MSCs (Figure 13). Interestingly, male TNFR1KO release of TNF, IL-6 and VEGF was significantly different from male WT, but not different from female WT as shown in Figure 13. Female WT MSCs did not significantly differ from female TNFR1KO MSC expression of VEGF.

Gender differences in MSC Apoptosis

Hypoxia induced significantly more apoptosis in WT male MSCs than in MSCs from WT female after 24 h incubation (Figure 4A). Interestingly, male TNFR1KO apoptosis was significantly lower than male WT, but not different from female WT and female TNFR1KO as shown in Figure 4B,C.

Figure 4
MSC apoptosis after hypoxia. A. Male and female WT, results expressed as absorbance (A405), mean ± SEM, *p<0.05 vs control. B. Male and female TNFR1KO, results expressed as absorbance (A405), mean ± SEM, *p<0.05 vs control. ...

DISCUSSION

The results of this study are the first demonstration that: 1) acute MSC activation via LPS and hypoxia results in local growth factor and pro-inflammatory cytokine expression; 2) activated female MSCs exhibit decreased apoptosis as well as decreased TNF, decreased IL-6, and increased VEGF expression; and 3) ablation of TNFR1 in males equalizes the female advantage in apoptosis and TNF, IL-6, and VEGF expression.

Adult mesenchymal stem cells may mediate their acute organ-protective effects via augmented angiogenesis and other complex paracrine effects. When transplanted into a foreign, inflammatory environment, MSCs may release substances which limit local inflammation in order to enhance its survival. Acute administration into injured tissue (which precluded immediate stem cell differentiation) of murine MSCs [7, 9]as well as human MSCs [8] improved function, decreased proinflammatory cytokine production, and decreased apoptosis. MSC therapy has been associated with protection via VEGF expression [21, 22]. In congruence, we found that MSC stimulation with LPS and hypoxia resulted in significant release of VEGF. Determining whether BMSC release of VEGF confers protection via reduced apoptosis [23], decreased proinflammatory cytokines [24], or other mechanistic pathways [25] requires further investigation. Thus, MSCs may enhance their own survival in addition to surrounding tissue by modulating local inflammation and stimulating endogenous repair mechanisms via the release of substances such as VEGF.

Recent studies have also shown that females experience a protective advantage following several forms of acute cardiac injury [2630]. Improved survival, less injury, and diminished inflammation are found in females when compared to males after ischemia-reperfusion (I/R) injury. [3133]. This study further addresses the influence of gender in the injury response. Female MSCs subjected to endotoxic or hypoxic injury demonstrated significantly greater VEGF expression than male MSCs. In correlation with the proposed inflammatory modulation via VEGF, female MSCs also exhibited less TNF and IL-6 expression in comparison to males after LPS and hypoxia. Female MSCs also demonstrated significantly less apoptosis than male MSCs after hypoxic injury. Rauscher et al demonstrated that BMSCs significantly decreased serum levels of IL-6, and limited atherosclerosis in a mouse atherosclerosis progression model [24]. Whether these increased levels of VEGF and decreased levels of TNF and IL-6 mediate protection is uncertain. Nevertheless, elevated VEGF production and decreased TNF and IL-6 expression by female MSC in the face of acute injury imply that female stem cells may have enhanced resistance to insult.

The role of TNF and the TNF receptor in stem cell function is complex and variable. It is now recognized that TNFR1 and/or TNFR2 engagement is essential for many of the biological responses of TNF. Both receptors exist in most cell types, including bone marrow stem cells [17]. In cardiac models, ablation of the TNFR1 gene blunts injury and improves survival, whereas ablation of the TNFR2 gene exacerbates injury and reduces survival [15]. This has led to the important appreciation that TNF may have beneficial or detrimental effects depending on which of its receptors is activated. In bone marrow stem cell function, this functional dichotomy in response to TNF has also been observed. While TNF may augment stem cell migration and chemoattraction [34], it also may inhibit stem cell proliferation, possibly via a TNFR1 mechanism [35]. Indeed, we observed that TNFR1 ablation significantly increases VEGF and decreases TNF and IL-6 expression in male MSCs, conferring a phenotypic MSC response in VEGF and TNF expression very similar to female MSCs. Further, TNFR1 ablation significantly reduced male MSC apoptosis after hypoxic injury. Thus, differential TNF receptor intracellular signaling may in part explain the gender differences in stem cell function described earlier. Targeting TNF signaling to increase anti-inflammatory and decrease in pro-inflammatory production may be of therapeutic value in the application of stem cell therapies.

It remains unclear what other mechanisms play a role in BMSC gender differences. Other progenitor cell populations may be differentially regulated by estrogen and progesterone, resulting in more progenitor cells in female derived primary cultures than males [36]. Interestingly, exogenous estrogen may also increase MSC function and calcium deposition [37]. Estrogen receptor alpha may be a target for estrogen and play a role in BMSC growth and differentiation [38] Mitogen activated protein kinases and cyclin dependent kinases may mediate the proliferative effect of estrogen on mouse embryonic stem cells [39]. Thus, it appears that estrogen which has been associated with greater protection found after acute cardiac injury, may also be associated with gender differences in BMSC activity. No study has addressed whether females may derive more benefit from stem cell therapy than males. However, if estrogen indeed plays a role in mediating BMSC activity and proliferation, one can hypothesize that females may have a therapeutic advantage regarding BMSC applications.

These results demonstrate that murine mesenchymal stem cells are significant sources of local paracrine factors such as the potentially protective VEGF and inflammatory TNF. Planned ischemic events such as those that occur during cardiac surgery, angioplasty, or transplantation may allow opportunity to observe the potential clinical benefit of adult stem cell therapies. However, gender discrepancies exist in mesenchymal stem cell function after injury, and injury induced TNF signaling via TNFR1 may have disparate effects in males and females. The attractive potential for the clinical application of stem cell therapy warrants further study to elucidate the mechanistic pathways to maximize stem cell paracrine protective factor expression such as VEGF and to minimize stem cell pro-inflammatory production such as TNF.

Footnotes

This work was supported in part by NIH R01GM070628 (DRM), and AHA Post-doctoral Fellowship 0526008Z (MW).

References

1. Nagy RD, Tsai BM, Wang M, Markel TA, Brown JW, Meldrum DR. Stem cell transplantation as a therapeutic approach to organ failure. J Surg Res. 2005 Nov;129(1):152–60. [PubMed]
2. Haider H, Ashraf M. Bone marrow cell transplantation in clinical perspective. J Mol Cell Cardiol. 2005 Feb;38(2):225–35. [PubMed]
3. Krause DS, Theise ND, Collector MI, Henegariu O, Hwang S, Gardner R, et al. Multi-organ, multi-lineage engraftment by a single bone marrow-derived stem cell. Cell. 2001 May 4;105(3):369–77. [PubMed]
4. Amado LC, Saliaris AP, Schuleri KH, St John M, Xie JS, Cattaneo S, et al. Cardiac repair with intramyocardial injection of allogeneic mesenchymal stem cells after myocardial infarction. Proc Natl Acad Sci U S A. 2005 Aug 9;102(32):11474–9. [PMC free article] [PubMed]
5. O'Neill TJt, Wamhoff BR, Owens GK, Skalak TC. Mobilization of bone marrow-derived cells enhances the angiogenic response to hypoxia without transdifferentiation into endothelial cells. Circ Res. 2005 Nov 11;97(10):1027–35. [PubMed]
6. Murry CE, Soonpaa MH, Reinecke H, Nakajima H, Nakajima HO, Rubart M, et al. Haematopoietic stem cells do not transdifferentiate into cardiac myocytes in myocardial infarcts. Nature. 2004 Apr 8;428(6983):664–8. [PubMed]
7. Togel F, Hu Z, Weiss K, Isaac J, Lange C, Westenfelder C. Administered mesenchymal stem cells protect against ischemic acute renal failure through differentiation-independent mechanisms. Am J Physiol Renal Physiol. 2005 Jul;289(1):F31–42. [PubMed]
8. Wang M, Tsai BM, Crisostomo PR, Meldrum DR. Pretreatment with Adult Progenitor Cells Improves Recovery and Decreases Native Myocardial Proinflammatory Signaling after Ischemia. Shock. 2006 May;25(5):454–9. [PubMed]
9. Uemura R, Xu M, Ahmad N, Ashraf M. Bone marrow stem cells prevent left ventricular remodeling of ischemic heart through paracrine signaling. Circ Res. 2006 Jun 9;98(11):1414–21. [PubMed]
10. Wang M, Baker L, Tsai BM, Meldrum KK, Meldrum DR. Sex Differences in the Myocardial Inflammatory Response to Ischemia/Reperfusion Injury. Am J Physiol Endocrinol Metab. 2005 Feb;288(2):E321–6. [PubMed]
11. Wang M, Tsai BM, Reiger KM, Brown JW, Meldrum DR. 17-beta-Estradiol decreases p38 MAPK-mediated myocardial inflammation and dysfunction following acute ischemia. J Mol Cell Cardiol. 2006 Feb;40(2):205–12. [PubMed]
12. Angele MK, Schwacha MG, Ayala A, Chaudry IH. Effect of gender and sex hormones on immune responses following shock. Shock. 2000 Aug;14(2):81–90. [PubMed]
13. Meldrum DR. Tumor necrosis factor in the heart. Am J Physiol. 1998 Mar;274(3 Pt 2):R577–95. [PubMed]
14. Kupatt C, Habazettl H, Goedecke A, Wolf DA, Zahler S, Boekstegers P, et al. Tumor necrosis factor-alpha contributes to ischemia- and reperfusion-induced endothelial activation in isolated hearts. Circ Res. 1999 Mar 5;84(4):392–400. [PubMed]
15. Oral H, Dorn GW, 2nd, Mann DL. Sphingosine mediates the immediate negative inotropic effects of tumor necrosis factor-alpha in the adult mammalian cardiac myocyte. J Biol Chem. 1997 Feb 21;272(8):4836–42. [PubMed]
16. Wang M, Tsai BM, Crisostomo PR, Meldrum DR. Tumor Necrosis Factor Receptor 1 Signaling Resistance In Female Myocardium During Ischemia. Circulation. 2006 In press. [PubMed]
17. Gerstenfeld LC, Cho TJ, Kon T, Aizawa T, Cruceta J, Graves BD, et al. Impaired intramembranous bone formation during bone repair in the absence of tumor necrosis factor-alpha signaling. Cells Tissues Organs. 2001;169(3):285–94. [PubMed]
18. Prockop DJ. Marrow stromal cells as stem cells for nonhematopoietic tissues. Science. 1997 Apr 4;276(5309):71–4. [PubMed]
19. Kudo M, Wang Y, Wani MA, Xu M, Ayub A, Ashraf M. Implantation of bone marrow stem cells reduces the infarction and fibrosis in ischemic mouse heart. J Mol Cell Cardiol. 2003 Sep;35(9):1113–9. [PubMed]
20. Peister A, Mellad JA, Larson BL, Hall BM, Gibson LF, Prockop DJ. Adult stem cells from bone marrow (MSCs) isolated from different strains of inbred mice vary in surface epitopes, rates of proliferation, and differentiation potential. Blood. 2004 Mar 1;103(5):1662–8. [PubMed]
21. Wang Y, Haider HK, Ahmad N, Xu M, Ge R, Ashraf M. Combining pharmacological mobilization with intramyocardial delivery of bone marrow cells over-expressing VEGF is more effective for cardiac repair. J Mol Cell Cardiol. 2006 May;40(5):736–45. [PubMed]
22. Hiasa K, Egashira K, Kitamoto S, Ishibashi M, Inoue S, Ni W, et al. Bone marrow mononuclear cell therapy limits myocardial infarct size through vascular endothelial growth factor. Basic Res Cardiol. 2004 May;99(3):165–72. [PubMed]
23. Rehman J, Traktuev D, Li J, Merfeld-Clauss S, Temm-Grove CJ, Bovenkerk JE, et al. Secretion of angiogenic and antiapoptotic factors by human adipose stromal cells. Circulation. 2004 Mar 16;109(10):1292–8. [PubMed]
24. Rauscher FM, Goldschmidt-Clermont PJ, Davis BH, Wang T, Gregg D, Ramaswami P, et al. Aging, progenitor cell exhaustion, and atherosclerosis. Circulation. 2003 Jul 29;108(4):457–63. [PubMed]
25. Wang M, Crisostomo PR, Herring C, Meldrum KK, Meldrum DR. Human progenitor cells from bone marrow or adipose tissue produce VEGF, HGF, and IGF-1 in response to TNF by a p38 mitogen activated protein kinase dependent mechanism. Am J Physiol Regul Integr Comp Physiol. 2006 In press. [PubMed]
26. Mizushima Y, Wang P, Jarrar D, Cioffi WG, Bland KI, Chaudry IH. Estradiol administration after trauma-hemorrhage improves cardiovascular and hepatocellular functions in male animals. Ann Surg. 2000 Nov;232(5):673–9. [PMC free article] [PubMed]
27. Szalay L, Shimizu T, Schwacha MG, Choudhry MA, Rue LW, 3rd, Bland KI, et al. Mechanism of salutary effects of estradiol on organ function after trauma-hemorrhage: upregulation of heme oxygenase. Am J Physiol Heart Circ Physiol. 2005 Jul;289(1):H92–8. [PubMed]
28. Baker L, Meldrum KK, Wang M, Sankula R, Vanam R, Raiesdana A, et al. The role of estrogen in cardiovascular disease. J Surg Res. 2003 Dec;115(2):325–44. [PubMed]
29. Kuebler JF, Toth B, Rue LW, 3rd, Wang P, Bland KI, Chaudry IH. Differential fluid regulation during and after soft tissue trauma and hemorrhagic shock in males and proestrus females. Shock. 2003 Aug;20(2):144–8. [PubMed]
30. Schwacha MG, Holland LT, Chaudry IH, Messina JL. Genetic variability in the immune-inflammatory response after major burn injury. Shock. 2005 Feb;23(2):123–8. [PubMed]
31. Szalay L, Shimizu T, Suzuki T, Yu HP, Choudhry MA, Schwacha MG, et al. Estradiol improves cardiac and hepatic function after trauma-hemorrhage: role of enhanced heat shock protein expression. Am J Physiol Regul Integr Comp Physiol. 2006 Mar;290(3):R812–8. [PubMed]
32. Yu HP, Shimizu T, Choudhry MA, Hsieh YC, Suzuki T, Bland KI, et al. Mechanism of cardioprotection following trauma-hemorrhagic shock by a selective estrogen receptor-beta agonist: up-regulation of cardiac heat shock factor-1 and heat shock proteins. J Mol Cell Cardiol. 2006 Jan;40(1):185–94. [PubMed]
33. Yu HP, Shimizu T, Hsieh YC, Suzuki T, Choudhry MA, Schwacha MG, et al. Tissue-specific expression of estrogen receptors and their role in the regulation of neutrophil infiltration in various organs following trauma-hemorrhage. J Leukoc Biol. 2006 May;79(5):963–70. [PubMed]
34. Chen Y, Ke Q, Yang Y, Rana JS, Tang J, Morgan JP, et al. Cardiomyocytes overexpressing TNF-alpha attract migration of embryonic stem cells via activation of p38 and c-Jun amino-terminal kinase. Faseb J. 2003 Dec;17(15):2231–9. [PubMed]
35. Zhang Y, Harada A, Bluethmann H, Wang JB, Nakao S, Mukaida N, et al. Tumor necrosis factor (TNF) is a physiologic regulator of hematopoietic progenitor cells: increase of early hematopoietic progenitor cells in TNF receptor p55-deficient mice in vivo and potent inhibition of progenitor cell proliferation by TNF alpha in vitro. Blood. 1995 Oct 15;86(8):2930–7. [PubMed]
36. Marin-Husstege M, Muggironi M, Raban D, Skoff RP, Casaccia-Bonnefil P. Oligodendrocyte progenitor proliferation and maturation is differentially regulated by male and female sex steroid hormones. Dev Neurosci. 2004 Mar–Aug;26(2–4):245–54. [PubMed]
37. Leskela HV, Olkku A, Lehtonen S, Mahonen A, Koivunen J, Turpeinen M, et al. Estrogen receptor alpha genotype confers interindividual variability of response to estrogen and testosterone in mesenchymal-stem-cell-derived osteoblasts. Bone. 2006 Jun 15 [PubMed]
38. Wang Q, Yu JH, Zhai HH, Zhao QT, Chen JW, Shu L, et al. Temporal expression of estrogen receptor alpha in rat bone marrow mesenchymal stem cells. Biochem Biophys Res Commun. 2006 Aug 18;347(1):117–23. [PubMed]
39. Han HJ, Heo JS, Lee YJ. Estradiol-17beta stimulates proliferation of mouse embryonic stem cells: involvement of MAPKs and CDKs as well as protooncogenes. Am J Physiol Cell Physiol. 2006 Apr;290(4):C1067–75. [PubMed]
PubReader format: click here to try

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...