LAMA2 regulates the fate commitment of mesenchymal stem cells via hedgehog signaling

Zhu, Yuan; Zhang, Xiao; Gu, Ranli; Liu, Xuenan; Wang, Siyi; Xia, Dandan; Li, Zheng; Lian, Xiaomin; Zhang, Ping; Liu, Yunsong

doi:10.1186/s13287-020-01631-9

“…The expression of both Lama2 and Lama4 was significantly higher in sWAT of the HFD group compared to the RCD group, by 5.9 and 4.0-fold respectively ( Figure 1B ). Lama2 , while predominantly expressed in muscle tissue and implicated in diseases of muscular dystrophy has also recently been shown to inhibit osteogenesis and promote adipogenesis of mesenchymal stem cells (MSCs) via the hedgehog signaling pathway ( 25 ). When relative Lama2 expression was compared to individual mouse weights at 16 weeks we found only a weak correlation (R 2 = 0.38) suggesting that Lama2 expression may not directly tie to adipose tissue mass in mice ( Figure 1C ).…”

Section: Resultsmentioning

confidence: 99%

Laminin-α4 Is Upregulated in Both Human and Murine Models of Obesity

Goddi

¹

,

Carmona

²

,

Schroedl

³

et al. 2021

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Obesity affects nearly one billion globally and can lead to life-threatening sequelae. Consequently, there is an urgent need for novel therapeutics. We have previously shown that laminin, alpha 4 (Lama4) knockout in mice leads to resistance to adipose tissue accumulation; however, the relationship between LAMA4 and obesity in humans has not been established. In this study we measured laminin-α chain and collagen mRNA expression in the subcutaneous white adipose tissue (sWAT) of mice placed on chow (RCD) or 45% high fat diet (HFD) for 8 weeks, and also in HFD mice then placed on a “weight loss” regimen (8 weeks HFD followed by 6 weeks RCD). To assess extracellular matrix (ECM) components in humans with obesity, laminin subunit alpha mRNA and protein expression was measured in sWAT biopsies of female control subjects (BMI<30) or subjects with obesity undergoing bariatric surgery at the University of Chicago Medical Center (BMI>35) both before and three months after surgery. Lama4 was significantly higher in sWAT of HFD compared to RCD mice at both the RNA and protein level (p<0.001, p<0.05 respectively). sWAT from human subjects with obesity also showed significantly higher LAMA4 mRNA (p<0.01) and LAMA4 protein expression (p<0.05) than controls. Interestingly, even though LAMA4 expression was increased in both humans and murine models of obesity, no significant difference in Lama4 or LAMA4 expression was detected following short-term weight loss in either mouse or human samples, respectively. From these results we propose a significant association between obesity and elevated LAMA4 expression in humans, as well as in mouse models of obesity. Further studies should clarify the mechanisms underlying this association to target LAMA4 effectively as a potential therapy for obesity.

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“…Interestingly, the induction of BMP2 and PTCH expression in undifferentiated SDC-1 KD cultures suggests the BMP and SHH signalling pathways are activated. BMP2 is a predominantly pro-osteogenic factor for hMSCs [44,45] and SHH signalling is also required for hMSC osteogenic differentiation [46,47]. When undifferentiated SDC-1 KD cultures were differentiated, these cultures appeared to have enhanced osteogenic differentiation, with increased von Kossa and Alizarin Red staining.…”

Section: Discussionmentioning

confidence: 99%

Syndecan-1 Facilitates the Human Mesenchymal Stem Cell Osteo-Adipogenic Balance

Yu¹,

Peall²,

Pham³

et al. 2020

IJMS

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Bone marrow-derived human mesenchymal stems cells (hMSCs) are precursors to adipocyte and osteoblast lineage cells. Dysregulation of the osteo-adipogenic balance has been implicated in pathological conditions involving bone loss. Heparan sulfate proteoglycans (HSPGs) such as cell membrane-bound syndecans (SDCs) and glypicans (GPCs) mediate hMSC lineage differentiation and with syndecan-1 (SDC-1) reported in both adipogenesis and osteogenesis, these macromolecules are potential regulators of the osteo-adipogenic balance. Here, we disrupted the HSPG profile in primary hMSC cultures via temporal knockdown (KD) of SDC-1 using RNA interference (RNAi) in undifferentiated, osteogenic and adipogenic differentiated hMSCs. SDC-1 KD cultures were examined for osteogenic and adipogenic lineage markers along with changes in HSPG profile and common signalling pathways implicated in hMSC lineage fate. Undifferentiated hMSC SDC-1 KD cultures exhibited a pro-adipogenic phenotype with subsequent osteogenic differentiation demonstrating enhanced maturation of osteoblasts. In cultures where SDC-1 KD was performed following initiation of differentiation, increased adipogenic gene and protein marker expression along with increased Oil Red O staining identified enhanced adipogenesis, with impaired osteogenesis also observed in these cultures. These findings implicate SDC-1 as a facilitator of the hMSC osteo-adipogenic balance during early induction of lineage differentiation.

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“…Mesenchymal stem cells (MSCs), which are multipotent mesenchymal cells present in various tissues, have multilineage differentiation ability under appropriate conditions and are easy to obtain. They are a promising therapeutic option for some diseases because of their unique property of releasing some important bioactive factors [ 3 – 5 ]. Drug toxicity can induce renal tubular epithelial cell damage or death and can lead to renal interstitial inflammation, which eventually develops into renal interstitial fibrosis and renal loss.…”

Section: Introductionmentioning

confidence: 99%

Nephroprotective Effect of Mesenchymal Stem Cell-Based Therapy of Kidney Disease Induced by Toxicants

Lin

¹

,

Lin

²

,

Liao

³

et al. 2020

Stem Cells International

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Background. Renal damage caused by drug toxicity is becoming increasingly common in the clinic. Preventing and treating kidney damage caused by drug toxicity are essential to maintain patient health and reduce the social and economic burden. In this study, we performed a meta-analysis to assess the nephroprotective effect of mesenchymal stem cells (MSCs) in the treatment of kidney disease induced by toxicants. Methods. The Cochrane Library, Embase, ISI Web of Science, and PubMed databases were searched up to December 31, 2019, to identify studies and extract data to assess the efficacy of MSCs treatment of kidney disease induced by toxicants using Cochrane Review Manager Version 5.3. A total of 27 studies were eligible and selected for this meta-analysis. Results. The results showed that a difference in serum creatinine levels between the MSC treatment group and control group was observed for 2, 4, 5, 6-8, 10-15, 28-30, and ≥42 days (2 days: WMD = − 0.88 , 95% CI: -1.34, -0.42, P = 0.0002 ; 4 days: WMD = − 0.74 , 95% CI: -0.95, -0.54, P < 0.00001 ; 5 days: WMD = − 0.46 , 95% CI: -0.67, -0.25, P < 0.0001 ; 6-8 days: WMD = − 0.55 , 95% CI: -0.84, -0.26, P = 0.0002 ; 10-15 days: WMD = − 0.37 , 95% CI: -0.53, -0.20, P < 0.0001 ; 28-30 days: WMD = − 0.53 , 95% CI: -1.04, -0.02, P = 0.04 ; ≥42 days: WMD = − 0.22 , 95% CI: -0.39, -0.06, P = 0.007 ). Furthermore, a difference in blood urea nitrogen levels between the MSC treatment group and control group was observed for 2-3, 4-5, 6-8, and ≥28 days. The results also indicate that MSC treatment alleviated inflammatory cells, necrotic tubules, regenerative tubules, and renal interstitial fibrosis in kidney disease induced by toxicants. Conclusion. MSCs may be a promising therapeutic agent for kidney disease induced by toxicants.

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LAMA2 regulates the fate commitment of mesenchymal stem cells via hedgehog signaling

Cited by 21 publications

References 49 publications

Laminin-α4 Is Upregulated in Both Human and Murine Models of Obesity

Laminin-α4 Is Upregulated in Both Human and Murine Models of Obesity

Syndecan-1 Facilitates the Human Mesenchymal Stem Cell Osteo-Adipogenic Balance

Nephroprotective Effect of Mesenchymal Stem Cell-Based Therapy of Kidney Disease Induced by Toxicants

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