Human progenitor cells from bone marrow or adipose tissue produce VEGF, HGF, and IGF-I in response to TNF by a p38 MAPK-dependent mechanism

Abstract

Accumulating evidence suggests that progenitor cells may decrease destructive inflammation and reduce tissue loss by antiapoptotic mechanisms. However, they remain poorly characterized, and many questions remain regarding the mechanisms by which they may positively affect wound healing, tissue remodeling, or tissue regeneration. It has been speculated that various growth factors are responsible, but what components of the wound milieu stimulate progenitor cell production of growth factors and by what mechanisms? We hypothesized that tumor necrosis factor-alpha (TNF-alpha) stimulated progenitor cell secretion of vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), and insulin-like growth factor I (IGF-I) by a p38 mitogen-activated protein kinase (MAPK)-dependent mechanism. Human mesenchymal stem cells (hMSCs) and human adipose progenitor cells (hAPCs) were divided into four groups: control, p38 MAPK inhibitor (p38MKI), TNF, and TNF + p38MKI. After 24 h of incubation, supernatants were harvested for ELISA of VEGF, HGF, and IGF-I. Cells were collected for Western blot analysis of p38 MAPK activation. Secretion of VEGF, HGF, and IGF-I in hMSCs and hAPCs was significantly increased by stimulation with TNF and was associated with increased activation of p38 MAPK. The p38 MAPK inhibitor decreased production of TNF-stimulated VEGF, HGF, and IGF-I in hMSCs and hAPCs. However, p38 MAPK inhibitor alone had no effect on production of growth factors. These data demonstrate that progenitor cells are potent sources of VEGF, HGF, and IGF-I. TNF, a prominent tissue cytokine, strongly stimulated production of growth factors by hMSCs and hAPCs via a p38 MAPK-dependent mechanism.

Adipose Tissue-Derived Stem Cells Treated with Estradiol Enhance Survival of Autologous Fat Transplants

“…MSCs have been widely studied and show great efficiency in clinical applications (Hong et al 2006(Hong et al , 2011. Previous studies have demonstrated that MSCs are able to produce various growth factors such as VEGF (Crisostomo et al 2007) and hepatocyte growth factor (Wang et al 2006) in vitro. These growth factors may promote angiogenesis (Wang et al 2006), decrease production of proinflammatory cytokines (Yang et al 2004(Yang et al , 2006 and reduce apoptosis (Ayala et al 1996(Ayala et al , 1998.…”

“…Previous studies have demonstrated that MSCs are able to produce various growth factors such as VEGF (Crisostomo et al 2007) and hepatocyte growth factor (Wang et al 2006) in vitro. These growth factors may promote angiogenesis (Wang et al 2006), decrease production of proinflammatory cytokines (Yang et al 2004(Yang et al , 2006 and reduce apoptosis (Ayala et al 1996(Ayala et al , 1998. However, MSC isolation from bone marrow remains a huge challenge and impedes their further development.…”

Células-tronco derivadas de tecido adiposo humano: desafios atuais e perspectivas clínicas

“…43 Moreover, ADSC secrete other potent growth factors, such as the vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), and growth factor-1, which is similar to insulin growth factor-1 (IGF-1). 44 The tumoral necrosis factor may significantly increase the secretion of VEGF, HGF, and IGF-1 of ADSC by the activation of p38, which is dependent on the protein kinase mechanism. 44 There are some molecular differences between ADSC and BMSC, although the profile of the expression of surface proteins [VII] and genes [VIII] appears to be similar 10,33 (Table 1).…”

“…44 The tumoral necrosis factor may significantly increase the secretion of VEGF, HGF, and IGF-1 of ADSC by the activation of p38, which is dependent on the protein kinase mechanism. 44 There are some molecular differences between ADSC and BMSC, although the profile of the expression of surface proteins [VII] and genes [VIII] appears to be similar 10,33 (Table 1). It is estimated that less than 1% of the genes are expressed differently by ADSC and BMSC.…”

Proinflammatory Stem Cell Signaling in Cardiac Ischemia

“…The primary pathways involved in proinflammatory MSC signaling include the nuclear factor kappa-B (NF-kB), mitogenactivated protein kinase (MAPK) family, Jak=STAT, and Akt= PI3K pathways (25,48,145,148). Understanding the key components of these signaling pathways may allow targeted therapeutic interventions to promote antiinflammatory pathways while mitigating proinflammatory signals.…”