Insulin-like growth factor binding protein-6 released from human mesenchymal stem cells confers neuronal protection through IGF-1R-mediated signaling

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Abstract

Human bone marrow-derived mesenchymal stem cells (hMSCs) are a desirable cell source for cell-based therapy to treat nervous system injuries due to their ability to differentiate into specific cell types. In addition to their multi-potency, hMSCs render the tissue microenvironment more favorable for tissue repair by secreting various growth factors. Our previous study demonstrated that hMSCs secrete several growth factors, including several insulin-like growth factor binding proteins (IGFBPs). Among these, IGFBP-6 binds with high affinity and inhibits insulin growth factor-2 (IGF-2) to inhibit the growth of IGF-2-dependent tumors. However, the function of IGFBP-6 in the nervous system remains to be fully elucidated. The present study investigated the protective effects of IGFBP-6 secreted by hMSCs on H ₂O ₂-injured primary cortical neuron cultures and lysolecithin-injured organotypic spinal cord slice cultures. Treatment of the H ₂O ₂-injured cortical neurons with conditioned media from hMSCs (hMSC-CM) increased the phosphorylation of Akt, reduced cell death and mitochondrial translocation of Bax, and regulated extracellular levels of IGF-1 and IGF-2. MTT assay, western blot analysis and ELISA were used to detect the cell viability and protein expression levels, respectively. An inhibitory antibody against IGFBP-6 eliminated this hMSC-CM-mediated neuroprotective effect in the injured cortical neuron cultures and spinal cord slice cultures. In addition, treatment with cyclolignan picropodophyllin, an inhibitor of IGF-1 receptor (IGF-1R), significantly inhibited neuronal protection by hMSC-CM. These findings demonstrated that hMSC-CM-mediated neuroprotection was attributed to IGF-1R-mediated signaling, potentiated via the inhibition of IGF-2 by IGFBP-6. The results of the present study provide insight into the mechanism by which hMSC administration may promote recovery from nerve injury.

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Most cited references 24

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The insulin-like growth factor-binding protein (IGFBP) superfamily.

V Hwa, Y. Oh, R Rosenfeld (1999)

Over the last decade, the concept of an IGFBP family has been well accepted, based on structural similarities and on functional abilities to bind IGFs with high affinities. The existence of other potential IGFBPs was left open. The discovery of proteins with N-terminal domains bearing striking structural similarities to the N terminus of the IGFBPs, and with reduced, but demonstrable, affinity for IGFs, raised the question of whether these proteins were "new" IGFBPs (22, 23, 217). The N-terminal domain had been uniquely associated with the IGFBPs and has long been considered to be critical for IGF binding. No other function has been confirmed for this domain to date. Thus, the presence of this important IGFBP domain in the N terminus of other proteins must be considered significant. Although these other proteins appear capable of binding IGF, their relatively low affinity and the fact that their major biological actions are likely to not directly involve the IGF peptides suggest that they probably should not be classified within the IGFBP family as provisionally proposed (22, 23). The conservation of this single domain, so critical to high-affinity binding of IGF by the six IGFBPs, in all of the IGFBP-rPs, as well, speaks to its biological importance. Historically, and perhaps, functionally, this has led to the designation of an "IGFBP superfamily". The classification and nomenclature for the IGFBP superfamily, are, of course, arbitrary; what is ultimately relevant is the underlying biology, much of which still remains to be deciphered. The nomenclature for the IGFBP related proteins was derived from a consensus of researchers working in the IGFBP field (52). Obviously, a more general consensus on nomenclature, involving all groups working on each IGFBP-rP, has yet to be reached. Further understanding of the biological functions of each protein should help resolve the nomenclature dilemma. For the present, redesignating these proteins IGFBP-rPs simplifies the multiple names already associated with each IGFBP related protein, and reinforces the concept of a relationship with the IGFBPs. Beyond the N-terminal domain, there is a lack of structural similarity between the IGFBP-rPs and IGFBPs. The C-terminal domains do share similarities to other internal domains found in numerous other proteins. For example, the similarity of the IGFBP C terminus to the thyroglobulin type-I domain shows that the IGFBPs are also structurally related to numerous other proteins carrying the same domain (87). Interestingly, the functions of the different C-terminal domains in members of the IGFBP superfamily include interactions with the cell surface or ECM, suggesting that, even if they share little sequence similarities, the C-terminal domains may be functionally related. The evolutionary conservation of the N-terminal domain and functional studies support the notion that IGFBPs and IGFBP-rPs together form an IGFBP superfamily. A superfamily delineates between closely related (classified as a family) and distantly related proteins. The IGFBP superfamily is therefore composed of distantly related families. The modular nature of the constituents of the IGFBP superfamily, particularly their preservation of an highly conserved N-terminal domain, seems best explained by the process of exon shuffling of an ancestral gene encoding this domain. Over the course of evolution, some members evolved into high-affinity IGF binders and others into low-affinity IGF binders, thereby conferring on the IGFBP superfamily the ability to influence cell growth by both IGF-dependent and IGF-independent means (Fig. 10). A final word, from Stephen Jay Gould (218): "But classifications are not passive ordering devices in a world objectively divided into obvious categories. Taxonomies are human decisions imposed upon nature--theories about the causes of nature's order. The chronicle of historical changes in classification provides our finest insight into conceptual revolutions

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Bcl-2, Bcl-X(L), and Bax are members of the Bcl-2 family that play key roles in the regulation of apoptosis. These proteins are believed to be membrane bound and their ability to undergo both homodimerization and heterodimerization has been proposed to regulate apoptosis. Herein we report that in murine thymocytes, Bcl-2 is exclusively membrane-bound, whereas Bax is present predominantly in the cytosol and Bcl-X(L) is present in both soluble and membrane-bound forms. Induction of apoptosis in murine thymocytes by dexamethasone or gamma-irradiation shifts the subcellular locations of Bax and Bcl-X(L) from soluble to membrane-bound forms. A similar shift in the localization of Bax from the cytosol to membranes was observed in HL-60 leukemia cells upon induction of apoptosis by staurosporine. Inhibition of apoptosis with cycloheximide inhibits the movement of Bax and Bcl-X(L) in thymocytes from the cytosol into membranes induced by dexamethasone treatment. These movements may represent an important step in the pathway by which members of this family regulate apoptosis.

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Ashley Reynolds, Chad Laurie, R Lee Mosley … (2007)

Microglia-derived inflammatory neurotoxins play a principal role in the pathogenesis of neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and HIV-associated dementia; chief among these is reactive oxygen species. The detrimental effects of oxidative stress in the brain and nervous system are primarily a result of the diminished capacity of the central nervous system to prevent ongoing oxidative damage. A spectrum of environmental cues, mitochondrial dysfunction, accumulation of aberrant misfolded proteins, inflammation, and defects in protein clearance are known to evolve and form as a result of disease progression. These factors likely affect glial function serving to accelerate the tempo of disease. Understanding the relationships between disease progression, free radical formation, neuroinflammation, and neurotoxicity is critical to elucidating disease mechanisms and the development of therapeutic modalities to combat disease processes. In an era where populations continue to age, the prevalence and incidence of age-related neurodegenerative diseases are on the rise; therefore, the need for novel therapeutic strategies that attenuate neuroinflammation and protect neurons against oxidative stress is ever more immediate.

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Author and article information

Journal

Journal ID (nlm-ta): Int J Mol Med

Journal ID (iso-abbrev): Int. J. Mol. Med

Journal ID (publisher-id): IJMM

Title: International Journal of Molecular Medicine

Publisher: D.A. Spandidos

ISSN (Print): 1107-3756

ISSN (Electronic): 1791-244X

Publication date (Print): December 2017

Publication date (Electronic): 05 October 2017

Publication date PMC-release: 05 October 2017

Volume: 40

Issue: 6

Pages: 1860-1868

Affiliations

[1 ]Laboratory of Stem Cell and Neurobiology, Department of Oral Anatomy, School of Dentistry and Dental Research Institute

[2 ]Neuroscience Research Institute, Seoul National University, Seoul 03080, Republic of Korea

Author notes

Correspondence to: Professor Mi-Sook Chang, Laboratory of Stem Cell and Neurobiology, Department of Oral Anatomy, School of Dentistry and Dental Research Institute, Seoul National University, 101 Daehak-ro, Jongno-gu, Seoul 03080, Republic of Korea, E-mail: mschang@ 123456snu.ac.kr

[*]

Contributed equally

Article

Publisher ID: ijmm-40-06-1860

DOI: 10.3892/ijmm.2017.3173

PMC ID: 5716453

PubMed ID: 29039467

SO-VID: ec5302c3-4ba9-4b34-ae4f-b723459a10a1

License:

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

History

Date received : 09 June 2017

Date accepted : 04 October 2017

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Insulin-like growth factor binding protein-6 released from human mesenchymal stem cells confers neuronal protection through IGF-1R-mediated signaling

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Abstract

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Stress signalling in stem cells

Most cited references 24

The insulin-like growth factor-binding protein (IGFBP) superfamily.

Cytosol-to-membrane redistribution of Bax and Bcl-X(L) during apoptosis.

Oxidative stress and the pathogenesis of neurodegenerative disorders.

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