Hyaluronan accumulation and arrested oligodendrocyte progenitor maturation in Vanishing White Matter disease

Bugiani, Marianna; Postma, Nienke L.; Polder, Emiel; Dieleman, Nikki; Scheffer, P; Sim, Fraser J.; Knaap, Marjo S. van der; Boor, Ilja

doi:10.1007/s12456-013-0028-8

Cited by 15 publications

(35 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The degree of white matter damage, the amounts of HMW hyaluronan locally present, and the increase in OPC numbers covary (21). Although previous studies (18,20,21) have suggested a role for astrocytes in the pathophysiology of VWM, this has not been confirmed. To explore the cellular pathophysiology of VWM and its dynamics throughout the disease course, and in view of future treatment strategies, we generated 2 new mutant mouse strains with a homozygous mutation in Eif2b4 or Eif2b5 and crossed them with double mutants.…”

Section: Introductionmentioning

confidence: 86%

“…Cocultures with 2b4 ho ACM showed a significantly lower number of MBP and MOGpositive cells than did cultures with WT ACM [n = 16, t(7) = 4.94, P < 0.01 and n = 16, t(7) = 3.12, P < 0.02, respectively; Figure 4, A-C]. In cocultures of 2b4 ho astro- One factor known to inhibit OPC maturation is hyaluronan (22), which is increased in the white matter of VWM patients (21). In mouse forebrain lysates, hyaluronan was significantly increased in 7-month-old 2b5 ho [n = 10, t(8) = -3.46, P < 0.01] and P21 2b4 ho 2b5 ho [n = 6, t(4) = -2.77, P = 0.05] (Supplemental Table 4) mice compared with agematched controls.…”

Section: White Matter Astrocytes In Vwm Are Immature and Have Abnormamentioning

confidence: 99%

“…Highmolecularweight (HMW) hyaluronan, an extracellular matrix component produced by astrocytes and known to inhibit OPC maturation (22), accumulates in VWM patients' white matter (21). The degree of white matter damage, the amounts of HMW hyaluronan locally present, and the increase in OPC numbers covary (21). Although previous studies (18,20,21) have suggested a role for astrocytes in the pathophysiology of VWM, this has not been confirmed.…”

Section: Introductionmentioning

confidence: 97%

“…Double transgenic animals with 1 homozygous mutation in Eif2b4 or Eif2b5 and 1 heterozygous mutation in the other eIF2B gene showed similar disease severity with respect to disease course, lifespan, and pathology and were grouped (2b42b5 he/ho mice (17)(18)(19)(20), immature (20,21), and overexpress the δisoform of GFAP (20). Lack of myelin coexists with strikingly increased numbers of premyelinating oligodendrocyte progenitor cells (OPCs) (20,21). Highmolecularweight (HMW) hyaluronan, an extracellular matrix component produced by astrocytes and known to inhibit OPC maturation (22), accumulates in VWM patients' white matter (21).…”

Section: Introductionmentioning

confidence: 99%

“…Lack of myelin coexists with strikingly increased numbers of premyelinating oligodendrocyte progenitor cells (OPCs) (20,21). Highmolecularweight (HMW) hyaluronan, an extracellular matrix component produced by astrocytes and known to inhibit OPC maturation (22), accumulates in VWM patients' white matter (21). The degree of white matter damage, the amounts of HMW hyaluronan locally present, and the increase in OPC numbers covary (21).…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Astrocytes are central in the pathomechanisms of vanishing white matter

Dooves¹,

Bugiani²,

Postma³

et al. 2016

Journal of Clinical Investigation

Self Cite

120

229

View full text Add to dashboard Cite

Section: Introductionmentioning

confidence: 86%

Section: White Matter Astrocytes In Vwm Are Immature and Have Abnormamentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Astrocytes are central in the pathomechanisms of vanishing white matter

Dooves¹,

Bugiani²,

Postma³

et al. 2016

Journal of Clinical Investigation

Self Cite

120

229

View full text Add to dashboard Cite

Astrocyte Subtype Vulnerability in Stem Cell Models of Vanishing White Matter

Leferink

Dooves

Hillen

et al. 2019

Annals of Neurology

View full text Add to dashboard Cite

Objective: Astrocytes have gained attention as important players in neurological disease. In line with their heterogeneous character, defects in specific astrocyte subtypes have been identified. Leukodystrophy vanishing white matter (VWM) shows selective vulnerability in white matter astrocytes, but the underlying mechanisms remain unclear. Induced pluripotent stem cell technology is being extensively explored in studies of pathophysiology and regenerative medicine. However, models for distinct astrocyte subtypes for VWM are lacking, thereby hampering identification of disease-specific pathways. Methods: Here, we characterize human and mouse pluripotent stem cell-derived gray and white matter astrocyte subtypes to generate an in vitro VWM model. We examined morphology and functionality, and used coculture methods, high-content microscopy, and RNA sequencing to study VWM cultures. Results: We found intrinsic vulnerability in specific astrocyte subpopulations in VWM. When comparing VWM and control cultures, white matter-like astrocytes inhibited oligodendrocyte maturation, and showed affected pathways in both human and mouse cultures, involving the immune system and extracellular matrix. Interestingly, human white matter-like astrocytes presented additional, human-specific disease mechanisms, such as neuronal and mitochondrial functioning. Interpretation: Astrocyte subtype cultures revealed disease-specific pathways in VWM. Cross-validation of human-and mouse-derived protocols identified human-specific disease aspects. This study provides new insights into VWM disease mechanisms, which helps the development of in vivo regenerative applications, and we further present strategies to study astrocyte subtype vulnerability in neurological disease.

show abstract

Adhesion G‐protein coupled receptors and extracellular matrix proteins: Roles in myelination and glial cell development

Mehta

Piao

2017

Developmental Dynamics

View full text Add to dashboard Cite

Background Adhesion G protein-coupled receptors (aGPCRs) are a large family of transmembrane proteins that play important roles in many processes during development, primarily through cell-cell and cell-extracellular matrix (ECM) interactions. In the nervous system, they have been linked to the complex process of myelination, both in the central and peripheral nervous system. Results GPR126 is essential in Schwann cell-mediated myelination in the peripheral nervous system (PNS), while GPR56 is involved in oligodendrocyte development central nervous system (CNS) myelination. VLGR1 is another aGPCR that is associated with the expression of myelin-associated glycoprotein (MAG) which has inhibitory effects on the process of nerve repair. The ECM is composed of a vast array of structural proteins, three of which interact specifically with aGPCRs: collagen III/GPR56, collagen IV/GPR126, and laminin-211/GPR126. Conclusions As druggable targets, aGPCRs are valuable in their ability to unlock treatment for a wide variety of currently debilitating myelin disorders.

show abstract

Hyaluronan accumulation and arrested oligodendrocyte progenitor maturation in Vanishing White Matter disease

Cited by 15 publications

References 0 publications

Astrocytes are central in the pathomechanisms of vanishing white matter

Astrocytes are central in the pathomechanisms of vanishing white matter

Astrocyte Subtype Vulnerability in Stem Cell Models of Vanishing White Matter

Adhesion G‐protein coupled receptors and extracellular matrix proteins: Roles in myelination and glial cell development

Contact Info

Product

Resources

About