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Early detection of structural abnormalities and cytoplasmic accumulation of TDP-43 in tissue-engineered skins derived from ALS patients.

Paré B, Touzel-Deschênes L, Lamontagne R, Lamarre MS, Scott FD, Khuong HT, Dion PA, Bouchard JP, Gould P, Rouleau GA, Dupré N, Berthod F, Gros-Louis F - Acta Neuropathol Commun (2015)

Bottom Line: As a result, the identification and development of disease-modifying therapies is difficult.Aiming to generate an innovative human-based model to facilitate the identification of predictive biomarkers associated with the disease, we developed a unique ALS tissue-engineered skin model (ALS-TES) derived from patient's own cells.Remarkably, these abnormal skin defects, uniquely seen in the ALS-derived skins, were detected in pre-symtomatic C9orf72-linked ALS patients carrying the GGGGCC DNA repeat expansion.

View Article: PubMed Central - PubMed

ABSTRACT
Amyotrophic lateral sclerosis (ALS) is an adult-onset disease characterized by the selective degeneration of motor neurons in the brain and spinal cord progressively leading to paralysis and death. Current diagnosis of ALS is based on clinical assessment of related symptoms. The clinical manifestations observed in ALS appear relatively late in the disease course after degeneration of a significant number of motor neurons. As a result, the identification and development of disease-modifying therapies is difficult. Therefore, novel strategies for early diagnosis of neurodegeneration, to monitor disease progression and to assess response to existing and future treatments are urgently needed. Factually, many neurological disorders, including ALS, are accompanied by skin changes that often precede the onset of neurological symptoms. Aiming to generate an innovative human-based model to facilitate the identification of predictive biomarkers associated with the disease, we developed a unique ALS tissue-engineered skin model (ALS-TES) derived from patient's own cells. The ALS-TES presents a number of striking features including altered epidermal differentiation, abnormal dermo-epidermal junction, delamination, keratinocyte infiltration, collagen disorganization and cytoplasmic TDP-43 inclusions. Remarkably, these abnormal skin defects, uniquely seen in the ALS-derived skins, were detected in pre-symtomatic C9orf72-linked ALS patients carrying the GGGGCC DNA repeat expansion. Consequently, our ALS skin model could represent a renewable source of human tissue, quickly and easily accessible to better understand the physiophatological mechanisms underlying this disease, to facilitate the identification of disease-specific biomarkers, and to develop innovative tools for early diagnosis and disease monitoring.

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Structural abnormalities detected in ALS-derived tissue engineered skins. a) Macroscopic pictures of control-derived and ALS-derived tissue-engineered skins when cultured at the air-liquid interface. b) Masson’s trichrome colorations, specifically staining the dermis (DE) in blue and epidermis (EP) in purple, revealed a number of structural abnormalities including undifferentiated epidermis, abnormal dermo-epidermal junctions, delamination, abnormal collagen organization, keratinocyte infiltration and cohesive failure of the stratum corneum (SC) in both C9orf72 FALS- and SALS-derived skins. In contrast control-derived reconstructed skins showed a well-developed and differentiated epidermis and highly organized dermis.
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Fig1: Structural abnormalities detected in ALS-derived tissue engineered skins. a) Macroscopic pictures of control-derived and ALS-derived tissue-engineered skins when cultured at the air-liquid interface. b) Masson’s trichrome colorations, specifically staining the dermis (DE) in blue and epidermis (EP) in purple, revealed a number of structural abnormalities including undifferentiated epidermis, abnormal dermo-epidermal junctions, delamination, abnormal collagen organization, keratinocyte infiltration and cohesive failure of the stratum corneum (SC) in both C9orf72 FALS- and SALS-derived skins. In contrast control-derived reconstructed skins showed a well-developed and differentiated epidermis and highly organized dermis.

Mentions: Masson’s trichrome is a special stain which is typically used to characterize and discriminate between various connective and soft tissue components. It is often utilized as the stain of choice of distinguishing histological changes in tumors, connective tissue diseases, muscle and fibroblast tumors, renal diseases and dermatology cases. Masson’s trichrome staining repeatedly revealed evident structural abnormalities uniquely detected in ALS-TES including an undifferentiated epidermis, cohesive failure of the stratum corneum, abnormal dermo-epidermal junction, delamination, keratinocyte infiltration, as well as collagen misorganization in both C9orf72 FALS- and SALS-derived skins (Figure 1 and Additional file 4: Table S2). In contrast, control-derived tissue engineered skins showed a well-developed and differentiated epidermis and highly organized dermis.Figure 1


Early detection of structural abnormalities and cytoplasmic accumulation of TDP-43 in tissue-engineered skins derived from ALS patients.

Paré B, Touzel-Deschênes L, Lamontagne R, Lamarre MS, Scott FD, Khuong HT, Dion PA, Bouchard JP, Gould P, Rouleau GA, Dupré N, Berthod F, Gros-Louis F - Acta Neuropathol Commun (2015)

Structural abnormalities detected in ALS-derived tissue engineered skins. a) Macroscopic pictures of control-derived and ALS-derived tissue-engineered skins when cultured at the air-liquid interface. b) Masson’s trichrome colorations, specifically staining the dermis (DE) in blue and epidermis (EP) in purple, revealed a number of structural abnormalities including undifferentiated epidermis, abnormal dermo-epidermal junctions, delamination, abnormal collagen organization, keratinocyte infiltration and cohesive failure of the stratum corneum (SC) in both C9orf72 FALS- and SALS-derived skins. In contrast control-derived reconstructed skins showed a well-developed and differentiated epidermis and highly organized dermis.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4359444&req=5

Fig1: Structural abnormalities detected in ALS-derived tissue engineered skins. a) Macroscopic pictures of control-derived and ALS-derived tissue-engineered skins when cultured at the air-liquid interface. b) Masson’s trichrome colorations, specifically staining the dermis (DE) in blue and epidermis (EP) in purple, revealed a number of structural abnormalities including undifferentiated epidermis, abnormal dermo-epidermal junctions, delamination, abnormal collagen organization, keratinocyte infiltration and cohesive failure of the stratum corneum (SC) in both C9orf72 FALS- and SALS-derived skins. In contrast control-derived reconstructed skins showed a well-developed and differentiated epidermis and highly organized dermis.
Mentions: Masson’s trichrome is a special stain which is typically used to characterize and discriminate between various connective and soft tissue components. It is often utilized as the stain of choice of distinguishing histological changes in tumors, connective tissue diseases, muscle and fibroblast tumors, renal diseases and dermatology cases. Masson’s trichrome staining repeatedly revealed evident structural abnormalities uniquely detected in ALS-TES including an undifferentiated epidermis, cohesive failure of the stratum corneum, abnormal dermo-epidermal junction, delamination, keratinocyte infiltration, as well as collagen misorganization in both C9orf72 FALS- and SALS-derived skins (Figure 1 and Additional file 4: Table S2). In contrast, control-derived tissue engineered skins showed a well-developed and differentiated epidermis and highly organized dermis.Figure 1

Bottom Line: As a result, the identification and development of disease-modifying therapies is difficult.Aiming to generate an innovative human-based model to facilitate the identification of predictive biomarkers associated with the disease, we developed a unique ALS tissue-engineered skin model (ALS-TES) derived from patient's own cells.Remarkably, these abnormal skin defects, uniquely seen in the ALS-derived skins, were detected in pre-symtomatic C9orf72-linked ALS patients carrying the GGGGCC DNA repeat expansion.

View Article: PubMed Central - PubMed

ABSTRACT
Amyotrophic lateral sclerosis (ALS) is an adult-onset disease characterized by the selective degeneration of motor neurons in the brain and spinal cord progressively leading to paralysis and death. Current diagnosis of ALS is based on clinical assessment of related symptoms. The clinical manifestations observed in ALS appear relatively late in the disease course after degeneration of a significant number of motor neurons. As a result, the identification and development of disease-modifying therapies is difficult. Therefore, novel strategies for early diagnosis of neurodegeneration, to monitor disease progression and to assess response to existing and future treatments are urgently needed. Factually, many neurological disorders, including ALS, are accompanied by skin changes that often precede the onset of neurological symptoms. Aiming to generate an innovative human-based model to facilitate the identification of predictive biomarkers associated with the disease, we developed a unique ALS tissue-engineered skin model (ALS-TES) derived from patient's own cells. The ALS-TES presents a number of striking features including altered epidermal differentiation, abnormal dermo-epidermal junction, delamination, keratinocyte infiltration, collagen disorganization and cytoplasmic TDP-43 inclusions. Remarkably, these abnormal skin defects, uniquely seen in the ALS-derived skins, were detected in pre-symtomatic C9orf72-linked ALS patients carrying the GGGGCC DNA repeat expansion. Consequently, our ALS skin model could represent a renewable source of human tissue, quickly and easily accessible to better understand the physiophatological mechanisms underlying this disease, to facilitate the identification of disease-specific biomarkers, and to develop innovative tools for early diagnosis and disease monitoring.

Show MeSH
Related in: MedlinePlus