Co-administration of human MSC overexpressing HIF-1a increases human CD34(+) cell engraftment in vivo.

Fecha de publicación: 07/12/2021 Fecha Ahead of Print: 07/12/2021

Autores de IIS La Fe

Pilar Sepúlveda Sanchis

Autor

Participantes ajenos a IIS La Fe

Preciado S
Sirerol-Piquer MS
Muntión S
Osugui L
Martí-Chillón GJ
Navarro-Bailón A
Sánchez-Guijo F

Grupos

Regeneración y Trasplante Cardíaco

Leader

Pilar Sepúlveda Sanchis

Abstract

BACKGROUND: Poor graft function or graft failure after allogeneic stem cell transplantation is an unmet medical need, in which mesenchymal stromal cells (MSC) constitute an attractive potential therapeutic approach. Hypoxia-inducible factor-1a (HIF-1a) overexpression in MSC (HIF-MSC) potentiates the angiogenic and immunomodulatory properties of these cells, so we hypothesized that co-transplantation of MSC-HIF with CD34(+) human cord blood cells would also enhance hematopoietic stem cell engraftment and function both in vitro and in vivo. METHODS: Human MSC were obtained from dental pulp. Lentiviral overexpression of HIF-1a was performed transducing cells with pWPI-green fluorescent protein (GFP) (MSC WT) or pWPI-HIF-1a-GFP (HIF-MSC) expression vectors. Human cord blood CD34(+) cells were co-cultured with MSC WT or HIF-MSC (4:1) for 72 h. Then, viability (Annexin V and 7-AAD), cell cycle, ROS expression and immunophenotyping of key molecules involved in engraftment (CXCR4, CD34, ITGA4, c-KIT) were evaluated by flow cytometry in CD34(+) cells. In addition, CD34(+) cells clonal expansion was analyzed by clonogenic assays. Finally, in vivo engraftment was measured by flow cytometry 4-weeks after CD34(+) cell transplantation with or without intrabone MSC WT or HIF-MSC in NOD/SCID mice. RESULTS: We did not observe significant differences in viability, cell cycle and ROS expression between CD34(+) cells co-cultured with MSC WT or HIF-MSC. Nevertheless, a significant increase in CD34, CXCR4 and ITGA4 expression (p = 0.009; p = 0.001; p = 0.013, respectively) was observed in CD34(+) cells co-cultured with HIF-MSC compared to MSC WT. In addition, CD34(+) cells cultured with HIF-MSC displayed a higher CFU-GM clonogenic potential than those cultured with MSC WT (p = 0.048). We also observed a significant increase in CD34(+) cells engraftment ability when they were co-transplanted with HIF-MSC compared to CD34(+) co-transplanted with MSC WT (p = 0.016) or alone (p = 0.015) in both the injected and contralateral femurs (p = 0.024, p = 0.008 respectively). CONCLUSIONS: Co-transplantation of human CD34(+) cells with HIF-MSC enhances cell engraftment in vivo. This is probably due to the ability of HIF-MSC to increase clonogenic capacity of hematopoietic cells and to induce the expression of adhesion molecules involved in graft survival in the hematopoietic niche.

Datos de la publicación

ISSN/ISSNe:: 1757-6512, 1757-6512
Tipo:: Article
Páginas:: 601-601
DOI:: 10.1186/s13287-021-02669-z
Factor de Impacto:: 1,330 SCImago ℠
Cuartil:: Q1 SCImago ℠

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Métricas

Filiaciones

Preciado S:: Cell Therapy Unit, Hematology Department, University Hospital of Salamanca, IBSAL, University of Salamanca, Paseo de San Vicente 58-182, 37007, Salamanca, Spain

RETIC TerCel, ISCIII, Madrid, Spain

Centro en Red de Medicina Regenerativa y Terapia Celular de Castilla y León, Salamanca, Spain
Sirerol-Piquer MS:: Departamento de Biología Celular, Biología Funcional y Antropología Física, University of Valencia, Burjassot, Spain

Instituto de Biotecnología y Biomedicina (BioTecMed), University of Valencia, Burjassot, Spain

RETIC TerCel, ISCIII, Madrid, Spain
Muntión S:: Cell Therapy Unit, Hematology Department, University Hospital of Salamanca, IBSAL, University of Salamanca, Paseo de San Vicente 58-182, 37007, Salamanca, Spain

RETIC TerCel, ISCIII, Madrid, Spain

Centro en Red de Medicina Regenerativa y Terapia Celular de Castilla y León, Salamanca, Spain
Osugui L:: Cell Therapy Unit, Hematology Department, University Hospital of Salamanca, IBSAL, University of Salamanca, Paseo de San Vicente 58-182, 37007, Salamanca, Spain

RETIC TerCel, ISCIII, Madrid, Spain

Centro en Red de Medicina Regenerativa y Terapia Celular de Castilla y León, Salamanca, Spain
Martí-Chillón GJ:: Cell Therapy Unit, Hematology Department, University Hospital of Salamanca, IBSAL, University of Salamanca, Paseo de San Vicente 58-182, 37007, Salamanca, Spain

RETIC TerCel, ISCIII, Madrid, Spain

Centro en Red de Medicina Regenerativa y Terapia Celular de Castilla y León, Salamanca, Spain
Navarro-Bailón A:: Cell Therapy Unit, Hematology Department, University Hospital of Salamanca, IBSAL, University of Salamanca, Paseo de San Vicente 58-182, 37007, Salamanca, Spain

RETIC TerCel, ISCIII, Madrid, Spain

Centro en Red de Medicina Regenerativa y Terapia Celular de Castilla y León, Salamanca, Spain
Sepúlveda P:: Regenerative Medicine and Heart Transplantation Unit, Instituto de Investigación Sanitaria La Fe, Valencia, Spain

RETIC TerCel, ISCIII, Madrid, Spain
Sánchez-Guijo F:: Cell Therapy Unit, Hematology Department, University Hospital of Salamanca, IBSAL, University of Salamanca, Paseo de San Vicente 58-182, 37007, Salamanca, Spain.

RETIC TerCel, ISCIII, Madrid, Spain.

Centro en Red de Medicina Regenerativa y Terapia Celular de Castilla y León, Salamanca, Spain.