Secreted trophic factors of Human umbilical cord stromal cells induce differentiation and neurite extension through PI3K and independent of cAMP pathway

Abstract

BackgroundTrophic factors (TFs) play important role during development and adult tissue maintenance. In neurodegenerative diseases (ND) TF supplementation provides protection. Stromal cells (HUMS) derived from the human umbilical cord matrix provide neuroprotection in the ND models of mice.PurposeThough TF mediated protection is known, the exact mechanism of protection is not clear. So, here the essential TFs (secreted by HUMS cells) and the pathway of induction of neurite extension, differentiation and networking is addressed.MethodsThe HUMS cells from the human umbilical cord matrix were derived and the mouse spinal cord motor neuron cell line, NSC-34 was extensively used. Flow cytometry, immunohistochemistry, RT- PCR, western blot, ELISA and antibody/inhibitor treatment were carried out to figure out the TF pathway.ResultsThe HUMS cells secrete six neurotrophic factors (sTFs), namely, NT-3, NGF, BDNF, VEGF, IGF-1 and GDNF (TFs). These TFs are sufficient to induce differentiation, neurite extension and neural networking in a motor neuron cell line, NSC34. All the 5 TFs need to be neutralized simultaneously with their antibodies to abrogate neurite extension. These motor neurons express the concomitant receptors, which are either receptor tyrosine kinase (TrK) coupled or to the receptor followed by the TrKs, for the above trophic factors (except for BDNF). The tyrosine kinase inhibitor, K252a, drastically reduces neurite extension. In NSC34, the TFs are coupled to the PI3K–Akt–pathway and the RAS-MAP kinase signaling through phosphorylation of ERK1 and ERK2. PI3K inhibitor, Ly 294002, abolishes neural differentiation and neurite extension. Thus, differentiation, neurite extension and networking could be achieved through the PI3K pathway. Intriguingly, the cAMP second messenger system coupling was not required. H89, PKA-inhibitor caused extensive cell death. But, had no effect in the presence of HUMS-secreted-TFs(HSTFs) suggesting a pathway switch for cell survival itself.ConclusionHUMS cells and their secreted factors could be of great use in regenerative medicine (RM). The activators of PI3K pathway, the major route of these HUMS-TFs action could be explored in RM and in the neurobiology of neural differentiation and extension.

Hematopoietic Stem Cells and Mesenchymal Stromal Cells in Acute Radiation Syndrome

“…With the development of cell-based therapies, it can make up for many of the drawbacks of cell replacement therapy, and the coordinated development of the two may benefit radiation-injured patients. For example, in recent years, HSC- and MSC-derived products have opened the door to develop new and innovative methods to reverse tissue damage caused by radiation as an alternative to cell transplants [ 99 , 102 ]. Moreover, with the further understanding of human tissues and organs, it is believed that the role of HSCs and MSCs in ARS will be further optimized in the future.…”

“…ECM produced by young cells can rejuvenate senescent cells by increasing their proliferation rate and differentiation potential [ 98 ]. Besides MSC-derived ECM, MSC-derived trophic factors (TFs) can also stimulate cell regeneration, promote tissue recovery, and protect cells from further injury [ 99 ].…”

The combined effect of mesenchymal stem cells and resveratrol on type 1 diabetic neuropathy

“…Reduced or absent expression of NGF may lead to cholinergic degeneration and cognitive impairment in rats, which indicates that NGF may serve as a therapeutic agent to protect or restore axonal branching and elongation (32–34). Growing evidence has suggested that numerous growth factors have dual neurotrophic and angiogenic effects, including vascular endothelial growth factor, insulin-like growth factor, NGF, brain derived neurotrophic factor and fibroblast growth factor-2, which are deficient in DN (35,36). It has been demonstrated that human MSCs are able to produce >84 trophic factors in conditioned medium and cell lysates (20).…”

The Proliferation Enhancing Effects of Salidroside on Schwann Cells In Vitro

“…The upregulated synthesis of BDNF, GDNF, and CDNF by treatment of salidroside might hold promising potential for the protection of cell viability. Binding to a small subset of receptors, including the tyrosine kinases TrkA, TrkB, and TrkC as well as neurotrophic receptor p75 (p75NTR), these neurotrophic factors are coupled to the PI3K/Akt pathway and the RAS-MAP kinase signaling through phosphorylation of ERK1 and ERK2 [ 38 ]. It has been reported that salidroside exerts neuroprotective effect by regulation of PI3K/Akt and RAS-MAP kinase signaling pathways [ 39 ].…”