Dataset Information

Unraveling the differential mechanisms of revascularization promoted by MSCs & ECFCs from adipose tissue or umbilical cord in a murine model of critical limb-threatening ischemia.

ABSTRACT: Critical limb threatening ischemia (CLTI), the most severe manifestation of peripheral artery disease, results from the chronic blockade of peripheral vessels, usually induced by atherosclerosis. CLTI patients suffer from high risk of amputation of the lower extremities and elevated mortality rates, while they have low options for surgical revascularization due to associated comorbidities. Alternatively, cell-based therapeutic strategies represent an effective and safe approach to promote revascularization and reversal of CLTI. However, the variety in cell types and cell combinations, administration routes or doses applied, have limited their success in clinical trials, being necessary to reach a consensus regarding the optimal “cellular-cocktail” for these patients, prior further application into the clinic. To achieve so, it is essential to understand the mechanisms by which these cells exert their regenerative properties. Herein, we have evaluated and compared, for the first time, the regenerative and vasculogenic potential of endothelial colony forming cells (ECFCs) isolated from either adipose-tissue (AT-ECFCs) or umbilical cord blood (CB-ECFCs), in combination with AT-derived MSCs, in a murine model of CLTI. Furthermore, the long-term molecular changes in CLTI and in response to both combinations have been analyzed in a proteomic quantitative approach. Overall, the administration of AT-MSCs with either AT- or CB-ECFCs, promoted a significant recovery of blood flow in CLTI mice 21 days post-ischemia, which appeared associated to an increased number of vessels in AT treated mice or with wider vessels in CB. Besides, they both modulated the inflammatory and necrotic processes, although the CB group presented the slowest ischemic progression along the assay. Furthermore, many of the protein changes identified are representative of the molecular mechanisms involved in ECFCs and MSCs induced revascularization (immune response, vascular repair, muscle regeneration, etc).

INSTRUMENT(S): Orbitrap Exploris 480

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Femoral Muscle

DISEASE(S): Limb Ischemia

SUBMITTER: Ana Martinez-Val

LAB HEAD: Jesper V. Olsen

PROVIDER: PXD046843 | Pride | 2024-07-25

REPOSITORIES: Pride

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			Action	DRS
	20220615_EXPL2_Evo7_MRT_SA_30SPD_DIA_Prot_Mouse_Muscle_A1_1.raw	Raw
	20220615_EXPL2_Evo7_MRT_SA_30SPD_DIA_Prot_Mouse_Muscle_A2_1.raw	Raw
	20220615_EXPL2_Evo7_MRT_SA_30SPD_DIA_Prot_Mouse_Muscle_A3_1.raw	Raw
	20220615_EXPL2_Evo7_MRT_SA_30SPD_DIA_Prot_Mouse_Muscle_A4_1.raw	Raw
	20220615_EXPL2_Evo7_MRT_SA_30SPD_DIA_Prot_Mouse_Muscle_A5_1.raw	Raw

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Unraveling the differential mechanisms of revascularization promoted by MSCs & ECFCs from adipose tissue or umbilical cord in a murine model of critical limb-threatening ischemia.

Rojas-Torres Marta M Beltrán-Camacho Lucía L Martínez-Val Ana A Sánchez-Gomar Ismael I Eslava-Alcón Sara S Rosal-Vela Antonio A Jiménez-Palomares Margarita M Doiz-Artázcoz Esther E Martínez-Torija Mario M Moreno-Luna Rafael R Olsen Jesper V JV Duran-Ruiz Ma Carmen MC

Journal of biomedical science 20240715 1

<h4>Background</h4>Critical limb-threatening ischemia (CLTI) constitutes the most severe manifestation of peripheral artery disease, usually induced by atherosclerosis. CLTI patients suffer from high risk of amputation of the lower extremities and elevated mortality rates, while they have low options for surgical revascularization due to associated comorbidities. Alternatively, cell-based therapeutic strategies represent an effective and safe approach to promote revascularization. However, the v ...[more]

PMID: 39004727

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Project description:Over-expression of wild type PrP in skeletal muscles is sufficient to cause a primary myopathy with no signs of peripheral neuropathy, possibly due to accumulation of a cytotoxic truncated form of PrP and/or PrP aggregation. In this study we used DNA microarrays to identify 1499 transcripts that are temporally deregulated concomitant with inducible PrPC over-expression in the skeletal muscles of transgenic mice. Examination using microarrays revealed a transcriptional profile with both similarities and differences to previously investigated models of myopathies. Down-regulation of genes coding for the myofibrillar proteins MYH2, MYH6, MYH7, MYL2, MYL3 and up-regulation of lysosomal genes CTSS, CTSD, CTSZ, DPEP2, HEXA, HEXB and LAMP1 coincide with the observed myopathy and lysosome accumulation on over-expression of PrPC. Down-regulation of the MEF2C gene, a key regulatory transcriptional factor muscle development and remodeling of adult muscles in response to physiologic and pathologic signals, may contribute to the centrally placed nuclei in the skeletal muscles. Significantly, up-regulation of genes involved in p53 signaling and the induction of p53 protein, suggest a central role for this molecule in the myopathy. Several p53-regulated genes involved in cell cycle arrest (CDNK1A, GADD45a and GADD45b) and apoptosis (BAK1, PMAIP1, BBC3, and BAX) are induced. We suggest that PrPC over-expression in skeletal muscles, possibly in response to accumulation of a cytotoxic truncated form of PrP, causes a primary myopathy involving the induction of p53-dependent pathways. Wild type (WT), PrP-null (KO), and Tg(HQK) mice were fed food pellets either lacking or containing 6g doxycycline (Dox)/kg food to induce PrPC expression. Skeletal muscles from the quadriceps of hind legs were removed at day 0, 4, 7, 14, 30 and 60 days following administration of Dox. Total RNA was isolated from these tissues for use in subsequent microarray analysis. Mouse gene expression was analysed by two-colour microarray experiments using an inhouse manufactured 16K mouse cDNA microarray. Age matched reference mice (WT) and experimental (KO and HQK) Alexa Flour labeled aRNA were used in each competitive hybridization. Each sample was labeled individually with both Alexa Fluor 555 and 647 for subsequent dye-swapped hybridizations to account for intensity bias. 3 individual mice from each experimental group at each time point were individually processed for separate microarrays. We used the program EDGE to identify genes that were differentially expressed in mouse skeletal muscle in either transgenic HQK mice over expressing PrP, or PrP knock out (KO) mice after administration of Dox. We used a P value cut-off of 0.05 as the criteria of selection of significantly differentially expressed genes.

Dataset Information

Unraveling the differential mechanisms of revascularization promoted by MSCs & ECFCs from adipose tissue or umbilical cord in a murine model of critical limb-threatening ischemia.

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Publications

Unraveling the differential mechanisms of revascularization promoted by MSCs & ECFCs from adipose tissue or umbilical cord in a murine model of critical limb-threatening ischemia.

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