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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-hMSC treatment led to host regeneration and muscle mass gain.(a) Haematoxylin and eosin (H&E) stain showed regenerating myofibers with centralized nuclei (black arrows) next to microvessels (white arrows) containing red blood cells (blue arrows) at day 14 in mice treated with 3.1-hMSCs+ILO or PGI2-hMSCs. (b) Muscle mass relative to body weight. Both 3.1-hMSCs+ILO- and PGI2-hMSC-treated mice had significant muscle mass gain in the gastrocnemius muscle in ischaemic hindlimbs as compared with the three other treatments after 1 month. **P<0.01, 3.1-hMSCs+ILO versus ILO, versus 3.1-hMSCs or versus PBS; *P<0.05, PGI2-hMSCs versus ILO, versus 3.1-hMSCs or versus PBS by a one-way ANOVA with Newman–Keuls post hoc test. Data are shown as mean±s.e.m. N=9 mice/PBS; N=5 mice/ILO; N=10 mice/3.1-hMSCs; N=10 mice/3.1-hMSCs+ILO; N=10 mice/PGI2-hMSCs. Both male and female mice were used. Scale bar, 20  μm.
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f3: PGI2-hMSC treatment led to host regeneration and muscle mass gain.(a) Haematoxylin and eosin (H&E) stain showed regenerating myofibers with centralized nuclei (black arrows) next to microvessels (white arrows) containing red blood cells (blue arrows) at day 14 in mice treated with 3.1-hMSCs+ILO or PGI2-hMSCs. (b) Muscle mass relative to body weight. Both 3.1-hMSCs+ILO- and PGI2-hMSC-treated mice had significant muscle mass gain in the gastrocnemius muscle in ischaemic hindlimbs as compared with the three other treatments after 1 month. **P<0.01, 3.1-hMSCs+ILO versus ILO, versus 3.1-hMSCs or versus PBS; *P<0.05, PGI2-hMSCs versus ILO, versus 3.1-hMSCs or versus PBS by a one-way ANOVA with Newman–Keuls post hoc test. Data are shown as mean±s.e.m. N=9 mice/PBS; N=5 mice/ILO; N=10 mice/3.1-hMSCs; N=10 mice/3.1-hMSCs+ILO; N=10 mice/PGI2-hMSCs. Both male and female mice were used. Scale bar, 20  μm.

Mentions: Because the improved treadmill running of mice that received PGI2-hMSCs was not due to long-term exogenous cell engraftment/differentiation in ischaemic hindlimbs, we studied how ischaemic muscle reacts to the treatment regimen by performing histological examinations. Histological examination of gastrocnemius muscle sections of ischaemic hindlimbs at 14 days after cell injections showed host muscle regeneration in PGI2-hMSC-treated mice (Fig. 3a) rather than cell engraftment. The newly formed myofibers had centralized nuclei and were located close to arterioles or capillaries (Fig. 3a). The presence of red blood cells within the arterioles or capillaries indicated the perfusion of oxygenated blood in the regenerated region. We also noted areas of new myofiber formation in the sections from mice treated with 3.1-hMSCs+ILO; however, few newly formed myofibers were seen with ILO, 3.1-hMSC or vehicle treatment (Fig. 3a). These findings suggest that exogenous PGI2-hMSCs or 3.1-hMSCs+ILO promoted endogenous regeneration in the gastrocnemius muscle of ischaemic hindlimbs (Fig. 3a).


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-hMSC treatment led to host regeneration and muscle mass gain.(a) Haematoxylin and eosin (H&E) stain showed regenerating myofibers with centralized nuclei (black arrows) next to microvessels (white arrows) containing red blood cells (blue arrows) at day 14 in mice treated with 3.1-hMSCs+ILO or PGI2-hMSCs. (b) Muscle mass relative to body weight. Both 3.1-hMSCs+ILO- and PGI2-hMSC-treated mice had significant muscle mass gain in the gastrocnemius muscle in ischaemic hindlimbs as compared with the three other treatments after 1 month. **P<0.01, 3.1-hMSCs+ILO versus ILO, versus 3.1-hMSCs or versus PBS; *P<0.05, PGI2-hMSCs versus ILO, versus 3.1-hMSCs or versus PBS by a one-way ANOVA with Newman–Keuls post hoc test. Data are shown as mean±s.e.m. N=9 mice/PBS; N=5 mice/ILO; N=10 mice/3.1-hMSCs; N=10 mice/3.1-hMSCs+ILO; N=10 mice/PGI2-hMSCs. Both male and female mice were used. Scale bar, 20  μm.
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f3: PGI2-hMSC treatment led to host regeneration and muscle mass gain.(a) Haematoxylin and eosin (H&E) stain showed regenerating myofibers with centralized nuclei (black arrows) next to microvessels (white arrows) containing red blood cells (blue arrows) at day 14 in mice treated with 3.1-hMSCs+ILO or PGI2-hMSCs. (b) Muscle mass relative to body weight. Both 3.1-hMSCs+ILO- and PGI2-hMSC-treated mice had significant muscle mass gain in the gastrocnemius muscle in ischaemic hindlimbs as compared with the three other treatments after 1 month. **P<0.01, 3.1-hMSCs+ILO versus ILO, versus 3.1-hMSCs or versus PBS; *P<0.05, PGI2-hMSCs versus ILO, versus 3.1-hMSCs or versus PBS by a one-way ANOVA with Newman–Keuls post hoc test. Data are shown as mean±s.e.m. N=9 mice/PBS; N=5 mice/ILO; N=10 mice/3.1-hMSCs; N=10 mice/3.1-hMSCs+ILO; N=10 mice/PGI2-hMSCs. Both male and female mice were used. Scale bar, 20  μm.
Mentions: Because the improved treadmill running of mice that received PGI2-hMSCs was not due to long-term exogenous cell engraftment/differentiation in ischaemic hindlimbs, we studied how ischaemic muscle reacts to the treatment regimen by performing histological examinations. Histological examination of gastrocnemius muscle sections of ischaemic hindlimbs at 14 days after cell injections showed host muscle regeneration in PGI2-hMSC-treated mice (Fig. 3a) rather than cell engraftment. The newly formed myofibers had centralized nuclei and were located close to arterioles or capillaries (Fig. 3a). The presence of red blood cells within the arterioles or capillaries indicated the perfusion of oxygenated blood in the regenerated region. We also noted areas of new myofiber formation in the sections from mice treated with 3.1-hMSCs+ILO; however, few newly formed myofibers were seen with ILO, 3.1-hMSC or vehicle treatment (Fig. 3a). These findings suggest that exogenous PGI2-hMSCs or 3.1-hMSCs+ILO promoted endogenous regeneration in the gastrocnemius muscle of ischaemic hindlimbs (Fig. 3a).

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