Angiopoietin-1 treated early endothelial outgrowth cells (eEOCs) are activated in vitro and reduce renal damage in murine acute ischemic kidney injury (iAKI)

Patschan, Daniel; Rinneburger, Jörg; Idrizi, Nazif; Backhaus, Rico; Schwarze, Katrin; Henze, Elvira; Patschan, Susann; Müller, Gerhard A.

doi:10.1186/1471-2369-14-227

Cited by 24 publications

(22 citation statements)

References 35 publications

(52 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…All protocols employed so far utilized intact cells, either without or after pharmacological preconditioning. Over the years we identified five distinct mediators that substantially improved the cells´ therapeutic competence in AKI [8,[15][16][17]21]. The current study, which avoided the injection of living cells did not confirm any of these observations.…”

Section: Discussioncontrasting

confidence: 58%

“…The discrepant findings possibly result from the artificial conditions that were used in our investigation. Felice and colleagues [27] exposed the cells to hypoxic conditions while we subjected PACs to specific mediators that were shown to significantly increase the AKI protective activity of intact cells [8,[15][16][17]. Regarding the fact that our study failed to show any beneficial effects of the secretome at all, the data substantially indicate that renoprotective effects of whole cells most likely require the mere presence of intact PACs in the kidney, especially if preconditioning protocols are in use.…”

Section: Discussionmentioning

confidence: 68%

“…Both components were either isolated from native cells or from stimulated PACs. Since previous own studies showed substantial PAC agonistic effects of Angiopoietin-1 / -2 [15,16], Bone Morphogenetic Protein-5 [17], and Melatonin [8], we decided to utilize each of these four mediators in an individual series of experiments. Therefore, we performed a total number of 15 interventional groups.…”

Section: Pac-induced Aki Protection Is Mediated By MV Derived From Nmentioning

confidence: 99%

See 2 more Smart Citations

PAC-mediated AKI protection is critically mediated but does not exclusively depend on cell-derived microvesicles

Dihazi¹,

Schwarze²,

Patschan³

et al. 2020

Preprint

View full text Add to dashboard Cite

Acute Kidney Injury (AKI) significantly worsens the prognosis of hospitalized patients. In recent years, cell-based strategies have been established as reliable option for improving AKI outcomes in experimental AKI. Own studies focused on so-called Proangiogenic Cells (PACs). Mechanisms that contribute to PAC-mediated AKI protection include production / secretion of extracellular vesicles (MV -microvesicles). In addition, the cells most likely act by paracrinic processes (secretome). The current study evaluated whether AKI may be preventable by the administration of either PAC-derived MV and / or the secretome alone. AKI was induced in male C57/Bl6N mice (8-12 weeks) by bilateral renal ischemia (IRI -40 minutes). Syngeneic murine PACs were stimulated with either melatonine, Angiopoietin-1 or -2, or with Bone Morphogenetic Protein-5 (BMP-5) for one hour, respectively. PACderived MV and the vesicle-depleted supernatant were subsequently collected and i.v. injected postischemia. Mice were analyzed 48 hours later. IRI induced significant kidney excretory dysfunction as reflected by higher serum cystatin C levels. The only measure that improved AKI was the injection of MV, collected from native PACs. The following conditions worsened post-ischemic renal function even further: MV+Ang-1, MV+BMP-5, MV+melatonin, and MV+secretome+Ang-1. Together, our data show that PAC-mediated AKI protection substantially depends on the availability of cell-derived MV. However, since previous data showed improved AKI-protection by PACs after cell preconditioning with certain mediators (Ang-1 and -2, melatonine, BMP-5), other than exclusively vesicle-dependent mechanisms must be involved in PAC-mediated AKI protection.

show abstract

Section: Discussioncontrasting

confidence: 58%

Section: Discussionmentioning

confidence: 68%

Section: Pac-induced Aki Protection Is Mediated By MV Derived From Nmentioning

confidence: 99%

See 1 more Smart Citation

PAC-mediated AKI protection is critically mediated but does not exclusively depend on cell-derived microvesicles

Dihazi¹,

Schwarze²,

Patschan³

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Thus, further studies were intended to augment the AKI-protective capacity of PACs and several pharmacological agonists of the cells were identified. Among those were melatonin [47], 8-O-cAMP [51], Bone Morphogenetic Protein-5 (BMP-5) [46], and Angiopoietin-1 [50] and -2 [49]. A more recent study showed that PACs administration post-AKI did not only prevent the kidney from acute loss of excretory function but also stabilizeed certain structural outcome parameters such as interstitial fibrosis and loss of peritubular capillaries [52].…”

Section: Proangiogenic Cells (Pacs) and Endothelial Colony Forming Cementioning

confidence: 99%

Cell-Based Therapies in Acute Kidney Injury (AKI)

Patschan

Buschmann

Ritter

et al. 2018

Kidney Blood Press Res

Self Cite

View full text Add to dashboard Cite

Acute kidney injury frequently occurs in hospitalized patients all over the world. The prognosis remains poor since specific therapies for promoting kidney regeneration/repair are still missing. In recent years cell-based strategies have improved AKI outcomes under experimental circumstances. Four groups of cells, each of them displaying certain biological and functional characteristics have been evaluated in AKI, induced Pluripotent Stem Cells (iPSCs), Spermatagonial Stem Cells (SSCs), Proangiogenic Cells (PACs) and Endothelial Colony Forming Cells (ECFCs), and Mesenchymal Stem Cells (MSCs). All of these have been documented to stabilize either parameters of kidney excretory dysfunction and/or certain morphological parameters. The mechanisms responsible for AKI protection include direct (cell incorporation) and indirect processes, the latter being mediated by humoral factors and particularly by the production of so-called extracellular vesicles. Cell-derived vesicular organelles have been shown to carry pro-regenerative micro-RNA molecules which stabilize the vascular and tubular function. The first trials in humans have been initiated, the majority of such trials employs MSCs. However, any transfer of cell-based strategies in the clinical practice is potentially associated with significant difficulties. These include cell availability, tolerance and competence. The article intends to summarize essential informations about all of the four populations mentioned above and to discuss implications for the management of human AKI.

show abstract

“…EPCs, and, in particular, early (e)EPCs [early endothelial outgrowth cells (12)], have experimentally been used in murine ischemic AKI (7, 18 -20, 22, 23, 25, 26). Several pharmacological strategies for eEPC preconditioning have been established in the meantime (18,19,22,23,26), allowing a more effective preservation of kidney function shortly after ischemia. Nevertheless, the overall prognosis in AKI does not only depend on renal dysfunction in the short term but also on chronic kidney damage in the mid to long term.…”

mentioning

confidence: 99%

The endothelial-to-mesenchymal transition and endothelial cilia in EPC-mediated postischemic kidney protection

Patschan

Schwarze

Henze

et al. 2016

American Journal of Physiology-Renal Physiology

View full text Add to dashboard Cite

Renal ischemia induces peritubular capillary rarefication and fibrosis, with the latter partly resulting from the endothelial-to-mesenchymal transition (EndoMT). Endothelial cilia transmit blood flow-associated forces into the cell. Early endothelial progenitor cells (eEPCs) have been shown to protect mice from acute kidney injury in the short term. The aim of the present study was to analyze midterm consequences of eEPC treatment in the context of endothelial cilia and the EndoMT. Male C57/Bl6N mice were subjected to unilateral renal ischemia postuninephrectomy. Syngeneic murine eEPCs were systemically injected at the time of reperfusion. Animals were investigated 1, 4, and 6 wk later. Cultured mature endothelial cells were exposed to a variable flow with versus without eEPC supernatant incubation. Systemically injected eEPCs reduced serum creatinine levels at (35 and 45 min) and (45 min). Interstitial fibrosis was significantly diminished by cell treatment at all time points as well. The EndoMT was less pronounced at (35 min) and (45 min). eEPC supernatant reduced α-smooth muscle actin expression and α-tubulin abundance in flow-treated cultured mature endothelial cells, and percentages of cilium-positive cells increased. The loss of peritubular capillaries was prevented by eEPCs. Intrarenal endothelial α-tubulin decreased postischemia and was further reduced by eEPC administration. We conclude that eEPCs are capable of reorganizing the endothelial cytoskeleton in an indirect manner, ultimately resulting in stabilization of the endothelial ciliome. The investigation indicates an antimesenchymal role of endothelial cilia in the process of postischemic tissue fibrosis/EndoMT.

show abstract

Angiopoietin-1 treated early endothelial outgrowth cells (eEOCs) are activated in vitro and reduce renal damage in murine acute ischemic kidney injury (iAKI)

Cited by 24 publications

References 35 publications

PAC-mediated AKI protection is critically mediated but does not exclusively depend on cell-derived microvesicles

PAC-mediated AKI protection is critically mediated but does not exclusively depend on cell-derived microvesicles

Cell-Based Therapies in Acute Kidney Injury (AKI)

The endothelial-to-mesenchymal transition and endothelial cilia in EPC-mediated postischemic kidney protection

Contact Info

Product

Resources

About