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Tissue Modeling in Systemic Sclerosis Using Induced Pluripotent Stem Cells (iPSCs) (hiPSSS)

11 de junho de 2026 atualizado por: University Hospital, Montpellier

The objective of the study is to establish an in vitro model using iPSCs to test the hypotheses developed.

The primary objective is to generate, via the SAFE-IPS platform, 8 iPSC lines derived from blood samples taken from:

  • Two patients with severe/diffuse SSc with multi-organ involvement (with anti-SCl-70 autoantibodies)
  • Two of their healthy close relatives
  • Two patients with uncomplicated SSc with localized involvement (with non-SCl-70 autoantibodies)
  • Two of their healthy close relatives

These 8 cell lines will be differentiated by several teams at the FHU REGENHAB into:

  • Immune cells (monocytes/macrophages, neutrophils, dendritic cells, B/T lymphocytes)
  • Mesenchymal stromal cells
  • Myocardial cells
  • Skin cells (fibroblasts)
  • Synovial cells
  • Bronchial cells
  • Endothelial cells

This project aims to map cellular and tissue heterogeneity using iPSC lines obtained from patients with both severe and mild SSc, employing single-cell RNA-seq under various pathological conditions, with and without autologous (or even heterologous) autoimmune stimulation. For example, the percentages of different cell types comprising a tissue in these various situations will be calculated. Comparisons will be made with control groups using healthy iPSC lines by recruiting healthy subjects with the same genetic profile and gender as the patients.

Visão geral do estudo

Status

Ainda não está recrutando

Condições

Intervenção / Tratamento

Descrição detalhada

Background:

Systemic sclerosis (SSc) is a rare autoimmune connective tissue disease that predominantly affects women, often has a severe course, and is characterized by heterogeneous multiorgan involvement. Its pathophysiology, involving microvascular abnormalities, autoimmune activation, and progressive fibrosis, remains incompletely understood, particularly regarding its variations across clinical forms and affected organs. Currently available treatments rely primarily on immunosuppressive strategies, which have limited efficacy and are associated with significant adverse effects, with no therapeutic option available to prevent certain major complications. In this context of unmet medical need, the use of induced pluripotent stem cells (iPSCs) derived from patients with SSc represents an innovative approach to modeling the pathophysiological mechanisms of the disease in vitro. The FHU Regenhab consortium's demonstrated ability to differentiate iPSCs into several relevant cell types offers a unique opportunity to study specific organ damage and identify new therapeutic targets, paving the way for more personalized treatment strategies.

Objectives:

Primary objective:

The primary objective is to generate, using the SAFE-IPS platform, 8 iPSC lines derived from cells obtained from a blood sample from:

  • Two patients with severe/diffuse SSc and multi-organ involvement (with anti-SCl-70 autoantibodies)
  • Two of their healthy close relatives
  • Two patients with uncomplicated SSc with localized involvement (with non-SCl-70 autoantibodies)
  • Two of their healthy close relatives

These 8 cell lines will be differentiated by several teams at the FHU REGENHAB into:

  • Immune cells (monocytes/macrophages, neutrophils, dendritic cells, B/T lymphocytes)
  • Mesenchymal stromal cells
  • Myocardial cells
  • Skin cells (fibroblasts)
  • Synovial cells
  • Bronchial cells
  • Endothelial cells This project aims to map cellular and tissue heterogeneity using iPSC lines by recruiting patients with severe and mild SSc, via single-cell RNA-seq, under various pathological conditions, with and without autologous (or even heterologous) autoimmune stimulation. For example, the percentages of different cell types comprising a tissue in these various situations will be calculated. Comparisons will be made with control groups using healthy iPSC lines by recruiting healthy subjects with the same genetic profile and gender as the patients.

Secondary objectives:

Signaling pathways and major biological processes that are differentially activated and suppressed under various conditions will be analyzed comparatively to better understand the extent to which the addition of the autoantibody alters cellular biology.

The identified signaling pathways will enable pharmacological modulation of differentiated tissue cultures. For example: if the ERK2/3 pathway is more active in differentiated tissues obtained from SSc patients compared to controls, as reported in Kim's publication (SCRT 2022), pharmacological modulation will be tested with and without the addition of autoantibodies. The tissue phenotype will be recharacterized using immunohistochemistry, conventional biochemistry for protein expression, and transcriptomic analysis.

Study Population:

A maximum of 8 patients will be enrolled, with the aim of having at least two evaluable patients per group: two patients with severe/diffuse SSc and two patients with localized/uncomplicated SSc. Enrollment will be halted once two iPSC lines differentiated into at least one target cell type have been obtained for each condition.

Investigators will simultaneously include healthy subjects without autoimmune diseases matched to each patient (n=8 maximum).

Inclusion criteria:

  • Age between 18 and 85 years
  • Participant agrees to have their biological samples and cell lines stored in a biological sample collection for other research purposes (including genetic research) on scleroderma

Severe SSc group:

  • Diagnosis of diffuse/severe SSc by a physician for at least 12 months based on guidelines (according to ACR criteria)
  • With known positivity for Scl-70 autoantibodies.

Localized/Uncomplicated SSc Group

  • Diagnosis of SSc by a physician for at least 12 months based on guidelines (according to ACR criteria)
  • Documentation of the absence of major involvement of vital organs
  • Negative anti-Scl-70 autoantibody but positive for other SSc Dot antibodies

Healthy Subjects Group

  • Relative of a patient enrolled in one of the scleroderma groups (father, mother, brother, sister, adult child)
  • Absence of systemic autoimmune diseases

Exclusion criteria:

  • Other diseases that may affect erythroid progenitor cells (non-exhaustive list: active cancer, malignant hematological disease, DNA-targeted chemotherapy)
  • Patient in an exclusion period determined by another protocol
  • Protected populations as defined by the French Public Health Code (women who are giving birth, breastfeeding, or pregnant; individuals deprived of their liberty by judicial or administrative decision; adults under legal protection (under any form of guardianship))
  • Lack of informed consent
  • Not covered by the national health insurance system

Tipo de estudo

Intervencional

Inscrição (Estimado)

16

Estágio

  • Não aplicável

Contactos e Locais

Esta seção fornece os detalhes de contato para aqueles que conduzem o estudo e informações sobre onde este estudo está sendo realizado.

Contato de estudo

Locais de estudo

Critérios de participação

Os pesquisadores procuram pessoas que se encaixem em uma determinada descrição, chamada de critérios de elegibilidade. Alguns exemplos desses critérios são a condição geral de saúde de uma pessoa ou tratamentos anteriores.

Critérios de elegibilidade

Idades elegíveis para estudo

  • Adulto
  • Adulto mais velho

Aceita Voluntários Saudáveis

Sim

Descrição

Inclusion Criteria:

  • Age between 18 and 85 years

  • Diagnostic criteria for the three groups:

    > Severe SSc group:

  • Diagnosis of diffuse/severe systemic sclerosis by a physician for at least 12 months based on recommendations (according to ACR criteria)

  • Known positivity of autoimmunity directed against Scl-70

    > Localized/non-complicated SSc group:

  • Diagnosis of systemic sclerosis by a physician for at least 12 months based on recommendations (according to ACR criteria)
  • Documentation of the absence of major vital organ involvement

  • Negative anti-Scl-70 autoantibodies but presence of other systemic sclerosis-related autoantibodies

    > Healthy subjects group:

  • First-degree relative of a patient recruited in one of the systemic sclerosis groups (father, mother, brother, sister, adult child)
  • Absence of systemic autoimmune diseases

Exclusion Criteria:

  • Other diseases that may affect erythroid progenitor cells (non-exhaustive: active cancer, hematological malignancy, chemotherapy targeting DNA)
  • Patient in an exclusion period determined by another protocol
  • Protected populations according to French public health law (pregnant or breastfeeding women; individuals deprived of liberty by judicial or administrative decision; adults under legal protection (any form of guardianship))
  • Absence of informed consent
  • Not affiliated with a national health insurance system

Plano de estudo

Esta seção fornece detalhes do plano de estudo, incluindo como o estudo é projetado e o que o estudo está medindo.

Como o estudo é projetado?

Detalhes do projeto

  • Finalidade Principal: Ciência básica
  • Alocação: N / D
  • Modelo Intervencional: Atribuição de grupo único
  • Mascaramento: Nenhum (rótulo aberto)

Armas e Intervenções

Grupo de Participantes / Braço
Intervenção / Tratamento
Experimental: Participants with Systemic Sclerosis and Healthy Controls
Participants undergo blood sample collection for generation of induced pluripotent stem cells (iPSCs) and in vitro cellular and tissue modeling.
Procedimento: Blood Sample Collection
Collection of approximately 28 mL of blood from each participant to generate induced pluripotent stem cell (iPSC) lines for in vitro cellular and tissue modeling analyses.

O que o estudo está medindo?

Medidas de resultados primários

Medida de resultado
Descrição da medida
Prazo
Rate of successful iPSC line generation from PBMCs in diffuse/severe systemic sclerosis patients
Prazo: At inclusion (Day 0 blood draw; iPSC generation assessed within approximately 3 months post-collection)

Percentage of participants with diffuse/severe systemic sclerosis (anti-Scl-70 positive) from whom at least one iPSC line is successfully generated via Sendai virus reprogramming of peripheral blood mononuclear cells (PBMCs).

Unit of Measure:

% of participants with at least one validated iPSC line
At inclusion (Day 0 blood draw; iPSC generation assessed within approximately 3 months post-collection)
Rate of successful differentiation of iPSCs into at least one target functional cell type in localized/non-complicated systemic sclerosis patients
Prazo: At inclusion (assessed within approximately 6 months post-collection)

Among validated iPSC lines from localized/non-complicated SSc patients, the percentage of lines achieving successful directed differentiation into at least one target cell type (cardiomyocytes, macrophages, bronchial epithelial cells, immune cells, or fibroblasts). Success is confirmed by cell-type-specific marker expression assessed by immunofluorescence and flow cytometry.

Unit of Measure:

% of validated iPSC lines successfully differentiated into ≥1 target cell type
At inclusion (assessed within approximately 6 months post-collection)
Rate of successful iPSC line generation from PBMCs in localized/non-complicated systemic sclerosis patients
Prazo: At inclusion (Day 0 blood draw; iPSC generation assessed within approximately 3 months post-collection)

Percentage of participants with localized/non-complicated systemic sclerosis (anti-Scl-70 negative, other SSc-specific antibody positive) from whom at least one iPSC line is successfully generated via Sendai virus reprogramming of PBMCs.

Unit of Measure:

% of participants with at least one validated iPSC line
At inclusion (Day 0 blood draw; iPSC generation assessed within approximately 3 months post-collection)
Rate of successful differentiation of iPSCs into at least one target functional cell type in diffuse/severe systemic sclerosis patients
Prazo: At inclusion (assessed within approximately 6 months post-collection)

Among validated iPSC lines from diffuse/severe SSc patients, the percentage of lines achieving successful directed differentiation into at least one target cell type (cardiomyocytes, macrophages, bronchial epithelial cells, immune cells, or fibroblasts). Success is confirmed by cell-type-specific marker expression assessed by immunofluorescence and flow cytometry (e.g., cTnT for cardiomyocytes; CD68/CSFR1 for macrophages; NKX2.1/MUC5AC for bronchial epithelium).

Unit of Measure:

% of validated iPSC lines successfully differentiated into ≥1 target cell type
At inclusion (assessed within approximately 6 months post-collection)

Medidas de resultados secundários

Medida de resultado
Descrição da medida
Prazo
Change in cardiomyocyte differentiation efficiency following autologous autoantibody exposure
Prazo: At inclusion

Comparison of ventricular cardiomyocyte differentiation efficiency, expressed as percentage of cardiac troponin T-positive (cTnT+) cells by flow cytometry, in iPSC-derived cardiomyocytes cultured with vs. without addition of autologous serum containing patient-specific autoantibodies. Serum is collected at Day 0 blood draw and stored at -80°C until use.

Unit of Measure:

% cTnT-positive cells (flow cytometry) - with vs. without autologous serum
At inclusion
Change in macrophage differentiation and inflammatory cytokine secretion following autologous autoantibody exposure
Prazo: At inclusion

Assessment of iPSC-derived macrophage phenotype (% CD68+, CSFR1+, CD163+ cells by flow cytometry) and inflammatory response (secretion of CCL2, IL-6, CXCL1, CXCL8 measured by ELISA in pg/mL) under baseline conditions and following addition of autologous autoantibody-containing serum, compared between SSc patient-derived and healthy control-derived macrophages.

Unit of Measure:

Cytokine concentration (pg/mL) by ELISA; % CD68+/CSFR1+ cells by flow cytometry
At inclusion
Functional characterization of iPSC-derived cardiomyocytes - spontaneous beating activity
Prazo: At inclusion

Proportion of iPSC-derived ventricular cardiomyocyte clusters exhibiting spontaneous contractile activity, assessed by video microscopy, as a measure of functional maturation following 2D differentiation and 3D spheroid formation using Matrigel. Maturation is further assessed after small molecule treatment with triiodothyronine (T3) and lipid-soluble cyclic AMP.

Unit of Measure:

% spontaneously beating clusters (video microscopy)
At inclusion
Molecular characterization of iPSC-derived cardiomyocytes - cardiac marker expression
Prazo: At inclusion

Assessment of cardiomyocyte identity by flow cytometry (% cardiac troponin T-positive cells) and RT-qPCR quantification of cardiac-specific genes (MYH6, MYH7, TNNI3, KCNH2) in iPSC-derived cardiomyocytes from SSc patients compared to healthy matched controls.

Unit of Measure:

% cTnT-positive cells (flow cytometry); relative gene expression (RT-qPCR, arbitrary units normalized to housekeeping gene)
At inclusion
Phenotypic characterization of iPSC-derived macrophages - pan-macrophage surface marker expression
Prazo: At inclusion

Quantification of pan-macrophage surface marker expression (CD68, CSFR1, CD163) by flow cytometry in iPSC-derived macrophages (iMACs) generated via embryoid body-based xeno-free protocol (Douthwaite et al., Bio Protoc. 2022). Pluripotency gene silencing is confirmed by RT-qPCR (SOX2, NANOG, OCT4 downregulation relative to parental iPSCs).

Unit of Measure:

% CD68+, % CSFR1+, % CD163+ cells (flow cytometry)
At inclusion
Transcriptomic characterization of iPSC-derived macrophages - inflammatory gene regulation
Prazo: At inclusion

Single-cell RNA sequencing-based characterization of iPSC-derived macrophage transcriptional programs, including quantification of pro-inflammatory gene expression (CCL2, CCL8, FASN, LPIN1, IL-6) under baseline and autoantibody-stimulated conditions. Transcriptomic profiles are compared between SSc patient-derived and healthy control-derived iMAC lines.

Unit of Measure:

Normalized gene expression counts (single-cell RNA sequencing, scRNA-seq)
At inclusion
Characterization of iPSC-derived immune cells - antigen-presenting cell differentiation efficiency
Prazo: At inclusion

Assessment of iPSC differentiation efficiency toward antigen-presenting cell lineages (dendritic cells and B/T lymphocyte precursors) using FLT3 overexpression-based differentiation protocol (Kitajima et al., Int. Immunol. 2023). Differentiation efficiency is quantified by flow cytometry using lineage-specific surface markers.

Unit of Measure:

% FLT3L-responsive antigen-presenting cell progenitors (flow cytometry)
At inclusion
Characterization of iPSC-derived bronchial epithelial cells - stepwise differentiation efficiency
Prazo: At inclusion

Stepwise quantification of bronchial epithelial differentiation efficiency by immunofluorescence at three sequential stages: (1) definitive endoderm: % CXCR4+/SOX17+/FOXA2+ cells; (2) bronchial progenitor stage: % NKX2.1+ cells negative for thyroid marker TG and forebrain marker FOXG1; (3) final air-liquid interface epithelium (iALI): % mucus-secreting cells (MUC5AC+) and % ciliated cells (acetylated alpha-tubulin+).

Unit of Measure:

% CXCR4+/SOX17+/FOXA2+ cells at endoderm stage; % NKX2.1+/TG-/FOXG1- cells at progenitor stage; % MUC5AC+ and % acetylated alpha-tubulin+ cells at final iALI stage (immunofluorescence)
At inclusion
Functional characterization of iPSC-derived bronchial air-liquid interface epithelium (iALI) - barrier integrity and mucociliary function
Prazo: At inclusion

Functional assessment of iPSC-derived air-liquid interface bronchial epithelium (iALI) obtained after 4-6 weeks of directed differentiation. Epithelial barrier integrity is quantified by transepithelial electrical resistance (TEER, ohm·cm²) on Transwell inserts. Mucociliary function is assessed by ciliary beat frequency measured by high-speed video microscopy (Hz). Results are compared between SSc patient-derived and healthy control-derived iALI cultures.

Unit of Measure:

Transepithelial electrical resistance (TEER, ohm·cm²); ciliary beat frequency (Hz, video microscopy)
At inclusion

Colaboradores e Investigadores

É aqui que você encontrará pessoas e organizações envolvidas com este estudo.

Patrocinador

University Hospital, Montpellier

Investigadores

  • Diretor de estudo: ARNAUD BOURDIN, MD, University Hospital, Montpellier

Datas de registro do estudo

Essas datas acompanham o progresso do registro do estudo e os envios de resumo dos resultados para ClinicalTrials.gov. Os registros do estudo e os resultados relatados são revisados ​​pela National Library of Medicine (NLM) para garantir que atendam aos padrões específicos de controle de qualidade antes de serem publicados no site público.

Datas Principais do Estudo

Início do estudo (Estimado)

1 de setembro de 2026

Conclusão Primária (Estimado)

1 de março de 2028

Conclusão do estudo (Estimado)

1 de março de 2028

Datas de inscrição no estudo

Enviado pela primeira vez

18 de maio de 2026

Enviado pela primeira vez que atendeu aos critérios de CQ

11 de junho de 2026

Primeira postagem (Real)

16 de junho de 2026

Atualizações de registro de estudo

Última Atualização Postada (Real)

16 de junho de 2026

Última atualização enviada que atendeu aos critérios de controle de qualidade

11 de junho de 2026

Última verificação

1 de junho de 2026

Mais Informações

Termos relacionados a este estudo

Palavras-chave

Termos MeSH relevantes adicionais

Outros números de identificação do estudo

  • RECHMPL24_0278
  • 2025-A02898-41 (Outro identificador: IdRCB)

Plano para dados de participantes individuais (IPD)

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