Genetic Engineering of Mesenchymal Stem Cells to Induce Their Migration and Survival

Nowakowski, Adam; Walczak, Piotr; Łukomska, Barbara; Janowski, Mirosław

doi:10.1155/2016/4956063

Cited by 59 publications

(47 citation statements)

References 95 publications

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“…Because the way of genetic modifications could achieve stable and long-term expression of targeted factors [33] and as shown in our previous study, Ang II enhance the migration of MSCs in an AT2R dependent way. Thus, we overexpressed AT2R in MSCs, using lentiviral vector, results in increased MSCs homing to injured lung of ARDS mice, which is consistent with existing literature using same genetic modifications strategy [19,34,35]. As a result, lung retention of MSCs genetically enhanced to overexpress AT2R are superior to that of control MSCs expressing reporter genes alone.…”

Section: Discussionsupporting

confidence: 88%

Genetic Modification of Mesenchymal Stem Cells Overexpressing Angiotensin II Type 2 Receptor Increases Cell Migration to Injured Lung in LPS-Induced Acute Lung Injury Mice

Huang

et al. 2018

Stem Cells Translational Medicine

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Although mesenchymal stem cells (MSCs) transplantation has been shown to promote the lung respiration in acute lung injury (ALI) in vivo, its overall restorative capacity appears to be restricted mainly because of low retention in the injured lung. Angiotensin II (Ang II) are upregulated in the injured lung. Our previous study showed that Ang II increased MSCs migration via Ang II type 2 receptor (AT2R). To determine the effect of AT2R in MSCs on their cell migration after systemic injection in ALI mice, a human AT2R expressing lentiviral vector and a lentivirus vector carrying AT2R shRNA were constructed and introduced into human bone marrow MSCs. A mouse model of lipopolysaccharide‐induced ALI was used to investigate the migration of AT2R‐regulated MSCs and the therapeutic potential in vivo. Overexpression of AT2R dramatically increased Ang II‐enhanced human bone marrow MSC migration in vitro. Moreover, MSC‐AT2R accumulated in the damaged lung tissue at significantly higher levels than control MSCs 24 and 72 hours after systematic MSC transplantation in ALI mice. Furthermore, MSC‐AT2R‐injected ALI mice exhibited a significant reduction of pulmonary vascular permeability and improved the lung histopathology and had additional anti‐inflammatory effects. In contrast, there were less lung retention in MSC‐ShAT2R‐injected ALI mice compared with MSC‐Shcontrol after transplantation. Thus, MSC‐ShAT2R‐injected group exhibited a significant increase of pulmonary vascular permeability and resulted in a deteriorative lung inflammation. Our results demonstrate that overexpression of AT2R enhance the migration of MSCs in ALI mice and may provide a new therapeutic strategy for ALI. Stem Cells Translational Medicine 2018;7:721–730

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Section: Discussionsupporting

confidence: 88%

Genetic Modification of Mesenchymal Stem Cells Overexpressing Angiotensin II Type 2 Receptor Increases Cell Migration to Injured Lung in LPS-Induced Acute Lung Injury Mice

Huang

et al. 2018

Stem Cells Translational Medicine

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“…Preconditioning and genetic modification of donor cells have been considered as a potential strategy to increase resistance to ischemic stress, ultimately boosting therapeutic efficacy. [48][49][50] Accordingly, our study shows that, although resident pericytes already provide an endogenous source of TPBG under ischemia, transplantation of TPBG-overexpressing APCs improved the hemodynamic recovery and reparative capillarization compared with spontaneous responses observed in control mice. A puzzling aspect of data in the Ad-Null APC injected group is represented by the improvement in blood Figure 8.…”

Section: Discussionmentioning

confidence: 52%

Role of TPBG (Trophoblast Glycoprotein) Antigen in Human Pericyte Migratory and Angiogenic Activity

Spencer

Jover

Cathery

et al. 2019

ATVB

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Objective-To determine the role of the oncofetal protein TPBG (trophoblast glycoprotein) in normal vascular function and reparative vascularization. Approach and Results-Immunohistochemistry of human veins was used to show TPBG expression in vascular smooth muscle cells and adventitial pericyte-like cells (APCs). ELISA, Western blot, immunocytochemistry, and proximity ligation assays evidenced a hypoxia-dependent upregulation of TPBG in APCs not found in vascular smooth muscle cells or endothelial cells. This involves the transcriptional modulator CITED2 (Atypical chemokine receptor 3 CBP/ p300-interacting transactivator with glutamic acid (E)/aspartic acid (D)-rich tail) and downstream activation of CXCL12 (chemokine [C-X-C motif] ligand-12) signaling through the CXCR7 (C-X-C chemokine receptor type 7) receptor and ERK1/2 (extracellular signal-regulated kinases 1/2). TPBG silencing by siRNA transfection downregulated CXCL12, CXCR7, and pERK (phospho Thr202/Tyr204 ERK1/2) and reduced the APC migratory and proangiogenic capacities. TPBG forced expression induced opposite effects, which were associated with the formation of CXCR7/CXCR4 (C-X-C chemokine receptor type 4) heterodimers and could be contrasted by CXCL12 and CXCR7 neutralization. In vivo Matrigel plug assays using APCs with or without TPBG silencing evidenced TPBG is essential for angiogenesis. Finally, in immunosuppressed mice with limb ischemia, intramuscular injection of TPBG-overexpressing APCs surpassed naïve APCs in enhancing perfusion recovery and reducing the rate of toe necrosis. Conclusions-TPBG orchestrates the migratory and angiogenic activities of pericytes through the activation of the CXCL12/ CXCR7/pERK axis. This novel mechanism could be a relevant target for therapeutic improvement of reparative angiogenesis. Visual Overview-An online visual overview is available for this article.

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“…This axis is also involved in stroke-induced neurogenesis (Merino et al 2015). There is also increasing evidence indicating that SDF-1 and its cellular receptor, CXCR-4, are also involved in guiding the migration of MSCs (Nowakowski et al 2016) and endothelial progenitor cells (EPCs) in response to injury (Figure 5) (Li et al 2012). The SDF-1–CXCR4 axis is also a “villain” in tumor metastasis (Weidle et al 2016).…”

Section: Other Major Migratory Pathways That Could Be Potentially Expmentioning

confidence: 99%

Migratory potential of transplanted glial progenitors as critical factor for successful translation of glia replacement therapy: The gap between mice and men

Srivastava

Bulte

Walczak

et al. 2017

Glia

Self Cite

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Neurological disorders are a major threat to public health. Stem cell-based regenerative medicine is now a promising experimental paradigm for its treatment, as shown in pre-clinical animal studies. Initial attempts have been on the replacement of neuronal cells only, but glial progenitors (GPs) are now becoming strong alternative cellular therapeutic candidates to replace oligodendrocytes and astrocytes as knowledge accumulates about their important emerging role in various disease processes. There are many examples of successful therapeutic outcomes for transplanted GPs in small animal models, but clinical translation has proved to be challenging due to the 1,000-fold larger volume of the human brain compared to mice. Human GPs transplanted into the mouse brain migrate extensively and can induce global cell replacement, but a similar extent of migration in the human brain would only allow for local rather than global cell replacement. We review here the mechanisms that govern cell migration, which could potentially be exploited to enhance the migratory properties of GPs through cell engineering pre-transplantation. We furthermore discuss the (dis)advantages of the various cell delivery routes that are available, with particular emphasis on intra-arterial injection as the most suitable route for achieving global cell distribution in the larger brain. Now that therapeutic success has proven to be feasible in small animal models, future efforts will need to be directed to enhance global cell delivery and migration to make bench-to-bedside translation a reality.

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Genetic Engineering of Mesenchymal Stem Cells to Induce Their Migration and Survival

Cited by 59 publications

References 95 publications

Genetic Modification of Mesenchymal Stem Cells Overexpressing Angiotensin II Type 2 Receptor Increases Cell Migration to Injured Lung in LPS-Induced Acute Lung Injury Mice

Genetic Modification of Mesenchymal Stem Cells Overexpressing Angiotensin II Type 2 Receptor Increases Cell Migration to Injured Lung in LPS-Induced Acute Lung Injury Mice

Role of TPBG (Trophoblast Glycoprotein) Antigen in Human Pericyte Migratory and Angiogenic Activity

Migratory potential of transplanted glial progenitors as critical factor for successful translation of glia replacement therapy: The gap between mice and men

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