Comunicación

HUMAN MESENCHYMAL STEM CELL-MEDIATED IMMUNOMODULATION IS BOOSTED BY CD44 LIGATION VIA ESCALATION OF IMMUNOREGULATORY MOLECULE PRODUCTION.

Autores:

DAVID GARCIA BERNAL1, MARINA CARPES RUIZ2, CARLOS MANUEL MARTINEZ CACERES2, ANA ISABEL GARCIA GUILLEN1, Miguel Blanquer Blanquer1, Ana María García Hernández3, MARIA DEL CARMEN ALGUERÓ MARTIN1, Robert Sackstein4, José Mª Moraleda Jiménez1

Afiliaciones:

(1) TRASPLANTE HEMATOPOYÉTICO / TERAPIA CELULAR, IMIB-Arrixaca, España
(2) PLATAFORMA DE PATOLOGÍA, IMIB-Arrixaca, España
(3) Instituto Murciano de Investigación Biosanitaria Virgen de la Arrixaca, 30120, España (Región de Murcia)
(4) Florida International University, Estados Unidos

Comunicación:

Antecedentes:

Mesenchymal stem cells (MSCs) are a multipotent progenitor cell population distributed throughout all tissues. In vitro, MSCs display potent anti-inflammatory/immunomodulatory properties. However, all MSCs lack molecular effectors of cell migration, being incapable of actively infiltrating inflammatory sites. It has been shown that enzymatic exofucosylation of the molecule CD44 on MSCs generates the potent E-selectin ligand HCELL, enabling in vivo MSC migration to endothelial beds that express E-selectin (i.e., bone marrow and inflamed tissues). However, apart from this augmented migration capacity, to date the immunobiology and functional properties of fucosylated MSCs has not been studied.

Métodos:

Isolation of human MSCs derived from adipose tissue (hAdMSCs) or bone marrow (hBMMSCs) was performed as described previously1. After, hAdMSCs or hBMMSCs were exofucosylated (“Fuc”: FuchAdMSCs or FuchBMMSCs) or buffer-treated (unmodified (“U”): UhAdMSCs or UhBMMSCs)2 and cultured in presence of different concentrations of E-selectin (mE-Ig) or hyaluronic acid (HA) for 3 days at 37ºC. Thereafter, culture supernatants were harvested and analyzed by ELISA for levels of anti-inflammatory molecules interleukin-10 (IL-10) and TGF, or IDO and nitric oxide metabolites (e.g., NO2-/NO3-). Cells cultured in the absence of HA or in presence of control IgG served as negative controls. Also, as controls to assess specificity of E-selectin binding, FuchAdMSCs or FuchBMMSCs were treated with sialidase (“sialFuchAdMSCs” or “sialFuchBMMSCs”) to cleave terminal sialic acid from sLex (thereby abrogating binding to E-selectin).

Resultados:

Both hAdMSCs and hBMMSCs each produced markedly higher levels of TGF, of IDO, and of NO metabolites after HCELL or CD44 ligation to E-selectin or HA, respectively (Fig. 1A,B). Importantly, CD44/HCELL ligation also profoundly boosted the production of the anti-inflammatory cytokine IL-10 by human MSCs from both marrow and adipose tissue sources (Fig. 1A). Notably, under stimulation by CD44/HCELL ligation with HA or E-selectin, respectively, production of all the immunomodulatory molecules tested was much higher in hAdMSCs than in hBMMSCs, especially for IL-10 (Fig. 1A, B, and Table 1). Indeed, in adipose-derived hMSCs, when analyzed as a ratio between IL-10 levels in hMSCs that engaged/did not engage either E-selectin or HA (i.e., ratio of FuchMSCs/UhMSCs for E-selectin exposure or of UhMSCs with HA exposure/UhMSCs without HA exposure), IL-10 production was heightened 10-fold by engagement of either HCELL (via E-selectin) or of CD44 (via HA). Furthermore, following CD44/HCELL ligation, adipose-derived hMSCs consistently showed >3-fold higher production of IL-10 compared to that of bone marrow-derived hMSCs (Table 1).

Conclusiones:

These findings indicate that CD44/HCELL ligation to HA and E-selectin, respectively, unleashes MSC immunobiologic properties indicating that fucosylated hMSCs may be a new safe and more effective cell therapy product for the treatment of immune-mediated disorders.


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Campus de Ciencias de la Salud
Carretera Buenavista s/n, 30120 El Palmar
Murcia, España

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