Restricted accessResearch articleFirst published online 2016-11
Receptor for Advanced Glycation End Products-Mediated Signaling Impairs the Maintenance of Bone Marrow Mesenchymal Stromal Cells in Diabetic Model Mice
Bone marrow mesenchymal stromal cells (BM-MSCs) have been demonstrated to contribute to tissue regeneration. However, chronic pathological conditions, such as diabetes and aging, can result in a decreased number and/or quality of BM-MSCs. We therefore investigated the maintenance mechanism of BM-MSCs by studying signaling through the receptor for advanced glycation end products (RAGE), which is thought to be activated under various pathological conditions. The abundance of endogenous BM-MSCs decreased in a type 2 diabetes mellitus (DM2) model, as determined by performing colony-forming unit (CFU) assays. Flow cytometric analysis revealed that the prevalence of the Lin−/ckit−/CD106+/CD44− BM population, which was previously identified as a slow-cycling BM-MSC population, also decreased. Furthermore, in a streptozotocin-induced type 1 DM model (DM1), the CFUs of fibroblasts and the prevalence of the Lin−/ckit−/CD106+/CD44− BM population also significantly decreased. BM-MSCs in RAGE knockout (KO) mice were resistant to such reduction induced by streptozotocin treatment, suggesting that chronic RAGE signaling worsened the maintenance mechanism of BM-MSCs. Using an in vitro culture condition, BM-MSCs from RAGE-KO mice showed less proliferation and expressed significantly more Nanog and Oct-4, which are key factors in multipotency, than did wild-type BM-MSCs. Furthermore, RAGE-KO BM-MSCs showed a greater capacity for differentiation into mesenchymal lineages, such as adipocytes and osteocytes. These data suggested that RAGE signaling inhibition is useful for maintaining BM-MSCs in vitro. Together, our findings indicated that perturbation of BM-MSCs in DM could be partially explained by chronic RAGE signaling and that targeting the RAGE signaling pathway is a viable approach for maintaining BM-MSCs under chronic pathological conditions.
Get full access to this article
View all access options for this article.
References
1.
FriedensteinAJ, DeriglasovaUF, KulaginaNN, PanasukAF, RudakowaSF, LuriaEA and RuadkowIA. (1974). Precursors for fibroblasts in different populations of hematopoietic cells as detected by the in vitro colony assay method. Exp Hematol, 2:83–92.
2.
PittengerMF, MackayAM, BeckSC, JaiswalRK, DouglasR, MoscaJD, MoormanMA, SimonettiDW, CraigS and MarshakDR. (1999). Multilineage potential of adult human mesenchymal stem cells. Science, 284:143–147.
3.
ProckopDJ. (1997). Marrow stromal cells as stem cells for nonhematopoietic tissues. Science, 276:71–74.
4.
ChoiH, LeeRH, BazhanovN, OhJY and ProckopDJ. (2011). Anti-inflammatory protein TSG-6 secreted by activated MSCs attenuates zymosan-induced mouse peritonitis by decreasing TLR2/NF-kappaB signaling in resident macrophages. Blood, 118:330–338.
5.
NemethK, LeelahavanichkulA, YuenPS, MayerB, ParmeleeA, DoiK, RobeyPG, LeelahavanichkulK, KollerBH, et al. (2009). Bone marrow stromal cells attenuate sepsis via prostaglandin E(2)-dependent reprogramming of host macrophages to increase their interleukin-10 production. Nat Med, 15:42–49.
6.
QuX, LiuX, ChengK, YangR and ZhaoRC. (2012). Mesenchymal stem cells inhibit Th17 cell differentiation by IL-10 secretion. Exp Hematol, 40:761–770.
7.
SquillaroT, PelusoG and GalderisiU. (2016). Clinical trials with mesenchymal stem cells: an update. Cell Transplant, 25:829–848.
8.
TsaiCC, SuPF, HuangYF, YewTL and HungSC. (2012). Oct4 and Nanog directly regulate Dnmt1 to maintain self-renewal and undifferentiated state in mesenchymal stem cells. Mol Cell, 47:169–182.
9.
YewTL, ChiuFY, TsaiCC, ChenHL, LeeWP, ChenYJ, ChangMC and HungSC. (2011). Knockdown of p21(Cip1/Waf1) enhances proliferation, the expression of stemness markers, and osteogenic potential in human mesenchymal stem cells. Aging Cell, 10:349–361.
10.
MorikawaS, MabuchiY, KubotaY, NagaiY, NiibeK, HiratsuE, SuzukiS, Miyauchi-HaraC, NagoshiN, et al. (2009). Prospective identification, isolation, and systemic transplantation of multipotent mesenchymal stem cells in murine bone marrow. J Exp Med, 206:2483–2496.
11.
LinSP, ChiuFY, WangY, YenML, KaoSY and HungSC. (2014). RB maintains quiescence and prevents premature senescence through upregulation of DNMT1 in mesenchymal stromal cells. Stem Cell Reports, 3:975–986.
12.
CiprianiP, GuiducciS, MiniatiI, CinelliM, UrbaniS, MarrelliA, DoloV, PavanA, SaccardiR, et al. (2007). Impairment of endothelial cell differentiation from bone marrow-derived mesenchymal stem cells: new insight into the pathogenesis of systemic sclerosis. Arthritis Rheum, 56:1994–2004.
13.
ShinL and PetersonDA. (2012). Impaired therapeutic capacity of autologous stem cells in a model of type 2 diabetes. Stem Cells Transl Med, 1:125–135.
14.
FujitaR, TamaiK, AikawaE, NimuraK, IshinoS, KikuchiY and KanedaY. (2015). Endogenous mesenchymal stromal cells in bone marrow are required to preserve muscle function in mdx mice. Stem Cells, 33:962–975.
15.
KoningJJ, KooijG, de VriesHE, NolteMA and MebiusRE. (2013). Mesenchymal stem cells are mobilized from the bone marrow during inflammation. Front Immunol, 4:49.
16.
TamaiK, YamazakiT, ChinoT, IshiiM, OtsuruS, KikuchiY, IinumaS, SagaK, NimuraK, et al. (2011). PDGFRalpha-positive cells in bone marrow are mobilized by high mobility group box 1 (HMGB1) to regenerate injured epithelia. Proc Natl Acad Sci U S A, 108:6609–6614.
17.
AikawaE, FujitaR, KikuchiY, KanedaY and TamaiK. (2015). Systemic high-mobility group box 1 administration suppresses skin inflammation by inducing an accumulation of PDGFRalpha(+) mesenchymal cells from bone marrow. Sci Rep, 5:11008.
18.
Soro-PaavonenA, WatsonAM, LiJ, PaavonenK, KoitkaA, CalkinAC, BaritD, CoughlanMT, DrewBG, et al. (2008). Receptor for advanced glycation end products (RAGE) deficiency attenuates the development of atherosclerosis in diabetes. Diabetes, 57:2461–2469.
19.
ParkL, RamanKG, LeeKJ, LuY, FerranLJJr., ChowWS, SternD and SchmidtAM. (1998). Suppression of accelerated diabetic atherosclerosis by the soluble receptor for advanced glycation endproducts. Nat Med, 4:1025–1031.
20.
MyintKM, YamamotoY, DoiT, KatoI, HarashimaA, YonekuraH, WatanabeT, ShinoharaH, TakeuchiM, et al. (2006). RAGE control of diabetic nephropathy in a mouse model: effects of RAGE gene disruption and administration of low-molecular weight heparin. Diabetes, 55:2510–2522.
21.
TeschG, SourrisKC, SummersSA, McCarthyD, WardMS, BorgDJ, GalloLA, FotheringhamAK, PettitAR, et al. (2014). Deletion of bone-marrow-derived receptor for AGEs (RAGE) improves renal function in an experimental mouse model of diabetes. Diabetologia, 57:1977–1985.
22.
LanderHM, TaurasJM, OgisteJS, HoriO, MossRA and SchmidtAM. (1997). Activation of the receptor for advanced glycation end products triggers a p21(ras)-dependent mitogen-activated protein kinase pathway regulated by oxidant stress. J Biol Chem, 272:17810–17814.
23.
OrigliaN, RighiM, CapsoniS, CattaneoA, FangF, SternDM, ChenJX, SchmidtAM, ArancioO, YanSD and DomeniciL. (2008). Receptor for advanced glycation end product-dependent activation of p38 mitogen-activated protein kinase contributes to amyloid-beta-mediated cortical synaptic dysfunction. J Neurosci, 28:3521–3530.
24.
DaffuG, del PozoCH, O'SheaKM, AnanthakrishnanR, RamasamyR and SchmidtAM. (2013). Radical roles for RAGE in the pathogenesis of oxidative stress in cardiovascular diseases and beyond. Int J Mol Sci, 14:19891–19910.
25.
KhanM, AliF, MohsinS, AkhtarS, MehmoodA, ChoudheryMS, KhanSN and RiazuddinS. (2013). Preconditioning diabetic mesenchymal stem cells with myogenic medium increases their ability to repair diabetic heart. Stem Cell Res Ther, 4:58.
26.
YanJ, TieG, WangS, MessinaKE, DiDatoS, GuoS and MessinaLM. (2012). Type 2 diabetes restricts multipotency of mesenchymal stem cells and impairs their capacity to augment postischemic neovascularization in db/db mice. J Am Heart Assoc, 1:e002238.
27.
KumeS, KatoS, YamagishiS, InagakiY, UedaS, ArimaN, OkawaT, KojiroM and NagataK. (2005). Advanced glycation end-products attenuate human mesenchymal stem cells and prevent cognate differentiation into adipose tissue, cartilage, and bone. J Bone Miner Res, 20:1647–1658.
28.
OtsuruS, TamaiK, YamazakiT, YoshikawaH and KanedaY. (2008). Circulating bone marrow-derived osteoblast progenitor cells are recruited to the bone-forming site by the CXCR4/stromal cell-derived factor-1 pathway. Stem Cells, 26:223–234.
29.
PierantozziE, GavaB, ManiniI, RovielloF, MarottaG, ChiavarelliM and SorrentinoV. (2011). Pluripotency regulators in human mesenchymal stem cells: expression of NANOG but not of OCT-4 and SOX-2. Stem Cells Dev, 20:915–923.
30.
MatsumotoA, TakeishiS, KanieT, SusakiE, OnoyamaI, TateishiY, NakayamaK and NakayamaKI. (2011). p57 is required for quiescence and maintenance of adult hematopoietic stem cells. Cell Stem Cell, 9:262–271.
31.
ZouP, YoshiharaH, HosokawaK, TaiI, ShinmyozuK, TsukaharaF, MaruY, NakayamaK, NakayamaKI and SudaT. (2011). p57(Kip2) and p27(Kip1) cooperate to maintain hematopoietic stem cell quiescence through interactions with Hsc70. Cell Stem Cell, 9:247–261.
32.
MonnierVM, SunW, SellDR, FanX, NemetI and GenuthS. (2014). Glucosepane: a poorly understood advanced glycation end product of growing importance for diabetes and its complications. Clin Chem Lab Med, 52:21–32.
33.
YangK, WangXQ, HeYS, LuL, ChenQJ, LiuJ and ShenWF. (2010). Advanced glycation end products induce chemokine/cytokine production via activation of p38 pathway and inhibit proliferation and migration of bone marrow mesenchymal stem cells. Cardiovasc Diabetol, 9:66.
34.
AsumdaFZ and ChasePB. (2011). Age-related changes in rat bone-marrow mesenchymal stem cell plasticity. BMC Cell Biol, 12:44.
35.
Kizilay ManciniO, Shum-TimD, StochajU, CorreaJA and ColmegnaI. (2015). Age, atherosclerosis and type 2 diabetes reduce human mesenchymal stromal cell-mediated T-cell suppression. Stem Cell Res Ther, 6:140.
36.
ChakkalakalJV, JonesKM, BassonMA and BrackAS. (2012). The aged niche disrupts muscle stem cell quiescence. Nature, 490:355–360.
37.
JuranekJK, GeddisMS, SongF, ZhangJ, GarciaJ, RosarioR, YanSF, BrannaganTH and SchmidtAM. (2013). RAGE deficiency improves postinjury sciatic nerve regeneration in type 1 diabetic mice. Diabetes, 62:931–943.
38.
LitwinoffE, Hurtado Del PozoC, RamasamyR and SchmidtAM. (2015). Emerging targets for therapeutic development in diabetes and its complications: the RAGE signaling pathway. Clin Pharmacol Ther, 98:135–144.
39.
McVicarCM, WardM, ColhounLM, Guduric-FuchsJ, BierhausA, FlemingT, SchlottererA, KolibabkaM, HammesHP, ChenM and StittAW. (2015). Role of the receptor for advanced glycation endproducts (RAGE) in retinal vasodegenerative pathology during diabetes in mice. Diabetologia, 58:1129–1137.
40.
ReinigerN, LauK, McCallaD, EbyB, ChengB, LuY, QuW, QuadriN, AnanthakrishnanR, et al. (2010). Deletion of the receptor for advanced glycation end products reduces glomerulosclerosis and preserves renal function in the diabetic OVE26 mouse. Diabetes, 59:2043–2054.
41.
LeeRH, SeoMJ, RegerRL, SpeesJL, PulinAA, OlsonSD and ProckopDJ. (2006). Multipotent stromal cells from human marrow home to and promote repair of pancreatic islets and renal glomeruli in diabetic NOD/scid mice. Proc Natl Acad Sci U S A, 103:17438–17443.
42.
LvS, ChengJ, SunA, LiJ, WangW, GuanG, LiuG and SuM. (2014). Mesenchymal stem cells transplantation ameliorates glomerular injury in streptozotocin-induced diabetic nephropathy in rats via inhibiting oxidative stress. Diabetes Res Clin Pract, 104:143–154.
43.
LiuY, LiZ, LiuT, XueX, JiangH, HuangJ and WangH. (2013). Impaired cardioprotective function of transplantation of mesenchymal stem cells from patients with diabetes mellitus to rats with experimentally induced myocardial infarction. Cardiovasc Diabetol, 12:40.
44.
IinumaS, AikawaE, TamaiK, FujitaR, KikuchiY, ChinoT, KikutaJ, McGrathJA, UittoJ, et al. (2015). Transplanted bone marrow-derived circulating PDGFRalpha+ cells restore type VII collagen in recessive dystrophic epidermolysis bullosa mouse skin graft. J Immunol, 194:1996–2003.
45.
van de VyverM, NieslerC, MyburghKH and FerrisWF. (2016). Delayed wound healing and dysregulation of IL6/STAT3 signalling in MSCs derived from pre-diabetic obese mice. Mol Cell Endocrinol, 426:1–10.
46.
ZhangX, PetersonKA, LiuXS, McMahonAP and OhbaS. (2013). Gene regulatory networks mediating canonical Wnt signal-directed control of pluripotency and differentiation in embryo stem cells. Stem Cells, 31:2667–2679.
47.
NowotnyK, JungT, HohnA, WeberD and GruneT. (2015). Advanced glycation end products and oxidative stress in type 2 diabetes mellitus. Biomolecules, 5:194–222.
48.
LiG, XuJ and LiZ. (2012). Receptor for advanced glycation end products inhibits proliferation in osteoblast through suppression of Wnt, PI3K and ERK signaling. Biochem Biophys Res Commun, 423:684–689.
49.
LanKC, ChiuCY, KaoCW, HuangKH, WangCC, HuangKT, TsaiKS, SheuML and LiuSH. (2015). Advanced glycation end-products induce apoptosis in pancreatic islet endothelial cells via NF-kappaB-activated cyclooxygenase-2/prostaglandin E2 up-regulation. PLoS One, 10:e0124418.
50.
YoonDS, KimYH, LeeS, LeeKM, ParkKH, JangY and LeeJW. (2014). Interleukin-6 induces the lineage commitment of bone marrow-derived mesenchymal multipotent cells through down-regulation of Sox2 by osteogenic transcription factors. FASEB J, 28:3273–3286.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
