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Prostacyclin-producing human mesenchymal cells target H19 lncRNA to augment endogenous progenitor function in hindlimb ischaemia.

Deng Y, Yang Z, Terry T, Pan S, Woodside DG, Wang J, Ruan K, Willerson JT, Dixon RA, Liu Q - Nat Commun (2016)

Bottom Line: Here we develop an innovative strategy to enhance the paracrine effects of hMSCs.Transplanted PGI2-hMSCs do not incorporate long term into host tissue, but rather they mediate host regeneration and muscle mass gain in a paracrine manner.Mechanistically, this involves long noncoding RNA H19 in promoting PGI2-hMSC-associated survival and proliferation of host progenitor cells under hypoxic conditions.

View Article: PubMed Central - PubMed

Affiliation: Wafic Said Molecular Cardiology Research Laboratory, Texas Heart Institute, P.O. Box 20345, MC 2-255, Houston, Texas 77225-0345, USA.

ABSTRACT
Promoting the paracrine effects of human mesenchymal stem cell (hMSC) therapy may contribute to improvements in patient outcomes. Here we develop an innovative strategy to enhance the paracrine effects of hMSCs. In a mouse hindlimb ischaemia model, we examine the effects of hMSCs in which a novel triple-catalytic enzyme is introduced to stably produce prostacyclin (PGI2-hMSCs). We show that PGI2-hMSCs facilitate perfusion recovery and enhance running capability as compared with control hMSCs or iloprost (a stable PGI2 analogue). Transplanted PGI2-hMSCs do not incorporate long term into host tissue, but rather they mediate host regeneration and muscle mass gain in a paracrine manner. Mechanistically, this involves long noncoding RNA H19 in promoting PGI2-hMSC-associated survival and proliferation of host progenitor cells under hypoxic conditions. Together, our data reveal the novel ability of PGI2-hMSCs to stimulate host regenerative processes and improve physical function by regulating long noncoding RNA in resident progenitor cells.

No MeSH data available.


Related in: MedlinePlus

PGI2-hMSCs did not affect the natural ability of hMSCs to release pro-survival and pro-angiogenic factors under hypoxia.(a) Representative images of proteome profiler arrays probed with 3.1-hMSC-conditioned medium (CM), 3.1-hMSCs+ILO-CM, or PGI2-hMSC-CM. (b) Analysis of the differential expression of angiogenic factors and chemokines from three independent arrays. CM collected from 3.1-hMSCs, 3.1-hMSCs+ILO or PGI2-hMSCs contained similar levels of soluble proteins known to promote survival and angiogenesis under ischaemic conditions. Data are shown as mean±s.e.m. from three independent arrays. CXCL16, chemokine (C–X–C motif) ligand 16; IGFBP1-3, insulin-like growth factor-binding protein 1-3; MCP-1, monocyte chemoattractant protein-1; PIGF, placental growth factor; TIMP-1, TIMP metallopeptidase inhibitor 1; TSP-1, thrombospondin-1; VEGF, vascular endothelial growth factor.
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f6: PGI2-hMSCs did not affect the natural ability of hMSCs to release pro-survival and pro-angiogenic factors under hypoxia.(a) Representative images of proteome profiler arrays probed with 3.1-hMSC-conditioned medium (CM), 3.1-hMSCs+ILO-CM, or PGI2-hMSC-CM. (b) Analysis of the differential expression of angiogenic factors and chemokines from three independent arrays. CM collected from 3.1-hMSCs, 3.1-hMSCs+ILO or PGI2-hMSCs contained similar levels of soluble proteins known to promote survival and angiogenesis under ischaemic conditions. Data are shown as mean±s.e.m. from three independent arrays. CXCL16, chemokine (C–X–C motif) ligand 16; IGFBP1-3, insulin-like growth factor-binding protein 1-3; MCP-1, monocyte chemoattractant protein-1; PIGF, placental growth factor; TIMP-1, TIMP metallopeptidase inhibitor 1; TSP-1, thrombospondin-1; VEGF, vascular endothelial growth factor.

Mentions: Given that native hMSCs exert pro-survival effects under ischaemia by secreting paracrine factors, we assessed whether the release of high levels of PGI2 from PGI2-hMSCs or the incubation of 3.1-hMSCs with ILO affects the secretion pattern of soluble proteins from hMSCs. Thus, we performed a proteome profiler array with conditioned media collected from cultures of PGI2-hMSCs, 3.1-hMSCs+ILO and 3.1-hMSCs that were grown without serum under hypoxic conditions (1.5% O2) mimicking the low-oxygen tension seen in ischaemic hindlimbs. We compared the simultaneous basal secretion of 54 soluble factors. The relative amounts of most factors in the conditioned medium of PGI2-hMSC and 3.1-hMSCs+ILO cultures were comparable to the levels from 3.1-hMSC cultures (Fig. 6a). Only a few factors showed subtle variations among the groups, and those results are given in Fig. 6b. Our findings suggest that PGI2 or ILO did not interfere with the natural ability of hMSCs to release high levels of cytoprotective, pro-survival and pro-angiogenic factors.


Prostacyclin-producing human mesenchymal cells target H19 lncRNA to augment endogenous progenitor function in hindlimb ischaemia.

Deng Y, Yang Z, Terry T, Pan S, Woodside DG, Wang J, Ruan K, Willerson JT, Dixon RA, Liu Q - Nat Commun (2016)

PGI2-hMSCs did not affect the natural ability of hMSCs to release pro-survival and pro-angiogenic factors under hypoxia.(a) Representative images of proteome profiler arrays probed with 3.1-hMSC-conditioned medium (CM), 3.1-hMSCs+ILO-CM, or PGI2-hMSC-CM. (b) Analysis of the differential expression of angiogenic factors and chemokines from three independent arrays. CM collected from 3.1-hMSCs, 3.1-hMSCs+ILO or PGI2-hMSCs contained similar levels of soluble proteins known to promote survival and angiogenesis under ischaemic conditions. Data are shown as mean±s.e.m. from three independent arrays. CXCL16, chemokine (C–X–C motif) ligand 16; IGFBP1-3, insulin-like growth factor-binding protein 1-3; MCP-1, monocyte chemoattractant protein-1; PIGF, placental growth factor; TIMP-1, TIMP metallopeptidase inhibitor 1; TSP-1, thrombospondin-1; VEGF, vascular endothelial growth factor.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4835554&req=5

f6: PGI2-hMSCs did not affect the natural ability of hMSCs to release pro-survival and pro-angiogenic factors under hypoxia.(a) Representative images of proteome profiler arrays probed with 3.1-hMSC-conditioned medium (CM), 3.1-hMSCs+ILO-CM, or PGI2-hMSC-CM. (b) Analysis of the differential expression of angiogenic factors and chemokines from three independent arrays. CM collected from 3.1-hMSCs, 3.1-hMSCs+ILO or PGI2-hMSCs contained similar levels of soluble proteins known to promote survival and angiogenesis under ischaemic conditions. Data are shown as mean±s.e.m. from three independent arrays. CXCL16, chemokine (C–X–C motif) ligand 16; IGFBP1-3, insulin-like growth factor-binding protein 1-3; MCP-1, monocyte chemoattractant protein-1; PIGF, placental growth factor; TIMP-1, TIMP metallopeptidase inhibitor 1; TSP-1, thrombospondin-1; VEGF, vascular endothelial growth factor.
Mentions: Given that native hMSCs exert pro-survival effects under ischaemia by secreting paracrine factors, we assessed whether the release of high levels of PGI2 from PGI2-hMSCs or the incubation of 3.1-hMSCs with ILO affects the secretion pattern of soluble proteins from hMSCs. Thus, we performed a proteome profiler array with conditioned media collected from cultures of PGI2-hMSCs, 3.1-hMSCs+ILO and 3.1-hMSCs that were grown without serum under hypoxic conditions (1.5% O2) mimicking the low-oxygen tension seen in ischaemic hindlimbs. We compared the simultaneous basal secretion of 54 soluble factors. The relative amounts of most factors in the conditioned medium of PGI2-hMSC and 3.1-hMSCs+ILO cultures were comparable to the levels from 3.1-hMSC cultures (Fig. 6a). Only a few factors showed subtle variations among the groups, and those results are given in Fig. 6b. Our findings suggest that PGI2 or ILO did not interfere with the natural ability of hMSCs to release high levels of cytoprotective, pro-survival and pro-angiogenic factors.

Bottom Line: Here we develop an innovative strategy to enhance the paracrine effects of hMSCs.Transplanted PGI2-hMSCs do not incorporate long term into host tissue, but rather they mediate host regeneration and muscle mass gain in a paracrine manner.Mechanistically, this involves long noncoding RNA H19 in promoting PGI2-hMSC-associated survival and proliferation of host progenitor cells under hypoxic conditions.

View Article: PubMed Central - PubMed

Affiliation: Wafic Said Molecular Cardiology Research Laboratory, Texas Heart Institute, P.O. Box 20345, MC 2-255, Houston, Texas 77225-0345, USA.

ABSTRACT
Promoting the paracrine effects of human mesenchymal stem cell (hMSC) therapy may contribute to improvements in patient outcomes. Here we develop an innovative strategy to enhance the paracrine effects of hMSCs. In a mouse hindlimb ischaemia model, we examine the effects of hMSCs in which a novel triple-catalytic enzyme is introduced to stably produce prostacyclin (PGI2-hMSCs). We show that PGI2-hMSCs facilitate perfusion recovery and enhance running capability as compared with control hMSCs or iloprost (a stable PGI2 analogue). Transplanted PGI2-hMSCs do not incorporate long term into host tissue, but rather they mediate host regeneration and muscle mass gain in a paracrine manner. Mechanistically, this involves long noncoding RNA H19 in promoting PGI2-hMSC-associated survival and proliferation of host progenitor cells under hypoxic conditions. Together, our data reveal the novel ability of PGI2-hMSCs to stimulate host regenerative processes and improve physical function by regulating long noncoding RNA in resident progenitor cells.

No MeSH data available.


Related in: MedlinePlus