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

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.

Knockout of beta‐2 microglobulin reduces stem cell‐induced immune rejection and enhances ischaemic hindlimb repair via exosome/miR‐24/Bim pathway

“…38 However, others showed that alloUMSCs do not induce immune rejection 39 using immunodeficient animal models. 26,27 In the present study, we demonstrate that human UMSCs trigger immune rejection in wild-type C57BL mice with normal immune system. Our findings are more clinically relevant because most patients who require stem cell transplantation are immunocompetent.…”

“…Perfusion was expressed as the perfusion ratio in the ischaemic leg compared with the contralateral, non-injured leg. 27 We focused our measurements on regional perfusion from ankle to toe because the extremities are most affected by ischaemic injury.…”

A novel single‐chain enzyme complex with chain reaction properties rapidly producing thromboxane A2 and exhibiting powerful anti‐bleeding functions

“…Therefore, a change in the distribution of PGH 2 to the particular isozyme is the key to control the metabolism of AA into the specific prostanoid. In recent years, using an enzymatic engineering approach to control the distribution of PGH 2 has been focused by our group to address this issue . In our previous studies, we have successfully created a single‐chain hybrid enzyme complex (SCHEC), COX‐1‐10aa‐PGIS, through the enzymatic engineering approach, which can force AA to be isomerized into PGI 2 , in order to rescue the deficiency of PGI 2 and to study the vascular protection effects of PGI 2 in cellular and animal models .…”

“…In recent years, using an enzymatic engineering approach to control the distribution of PGH 2 has been focused by our group to address this issue. [10][11][12][13][14][15][16][17] In our previous studies, we have successfully created a single-chain hybrid enzyme complex (SCHEC), COX-1-10aa-PGIS, through the enzymatic engineering approach, which can force AA to be isomerized into PGI 2 , in order to rescue the deficiency of PGI 2 and to study the vascular protection effects of PGI 2 in cellular and animal models. [10][11][12][13] Another SCHEC, COX-2-10aa-mPGES-1, which can effectively pass PGH 2 to mPGES-1, to convert AA to PGE 2 , has also been created as a model for understanding how PGE 2 is biosynthesized during inflammation.…”

“…[10][11][12][13][14][15][16][17] In our previous studies, we have successfully created a single-chain hybrid enzyme complex (SCHEC), COX-1-10aa-PGIS, through the enzymatic engineering approach, which can force AA to be isomerized into PGI 2 , in order to rescue the deficiency of PGI 2 and to study the vascular protection effects of PGI 2 in cellular and animal models. [10][11][12][13] Another SCHEC, COX-2-10aa-mPGES-1, which can effectively pass PGH 2 to mPGES-1, to convert AA to PGE 2 , has also been created as a model for understanding how PGE 2 is biosynthesized during inflammation. [14][15][16][17][18] In this study, we created a novel SCHEC, linking the C-terminus of COX-1 to the N-terminus of the TXAS, through a 10-residue amino acid linker, to directly guide the metabolism of AA to TXA 2 by effectively passing the COX-1 produced PGH 2 to TXAS.…”