iPSC-derived endothelial cell response to hypoxia via SDF1a/CXCR4 axis facilitates incorporation to revascularize ischemic retina

Cho, Hongkwan; Macklin, Bria; Lin, Ying; Zhou, Lingli; Lai, Michael J.; Lee, Grace; Gerecht, Sharon; Duh, Elia J.

doi:10.1172/jci.insight.131828

Cited by 31 publications

(28 citation statements)

References 27 publications

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“…Human iPSC derived from cord blood could generate vascular progenitor cells, which exhibited homing and integration into injured retinal vessels for up to 45 days [ 188 ]. Human iPSC-derived endothelial cells formed more complex vascular networks in vitro and integrated into host regenerating retinal vessels in a mouse model of ischemic retinopathies when compared to human mature endothelial cells, suggesting its superior angiogenic potential in ischemic retinopathies (such as proliferative DR) [ 189 ]. One clinical trial (NCT03403699) is evaluating the ability of human iPSC to generate endothelial cells and pericytes for revascularization of vasodegenerative capillaries occurring in DR.…”

Section: Main Textmentioning

confidence: 99%

Neurovascular unit in diabetic retinopathy: pathophysiological roles and potential therapeutical targets

Shen¹,

Lo²,

Mi³

et al. 2021

Eye and Vis

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Diabetic retinopathy (DR), one of the common complications of diabetes, is the leading cause of visual loss in working-age individuals in many industrialized countries. It has been traditionally regarded as a purely microvascular disease in the retina. However, an increasing number of studies have shown that DR is a complex neurovascular disorder that affects not only vascular structure but also neural tissue of the retina. Deterioration of neural retina could precede microvascular abnormalities in the DR, leading to microvascular changes. Furthermore, disruption of interactions among neurons, vascular cells, glia and local immune cells, which collectively form the neurovascular unit, is considered to be associated with the progression of DR early on in the disease. Therefore, it makes sense to develop new therapeutic strategies to prevent or reverse retinal neurodegeneration, neuroinflammation and impaired cell-cell interactions of the neurovascular unit in early stage DR. Here, we present current perspectives on the pathophysiology of DR as a neurovascular disease, especially at the early stage. Potential novel treatments for preventing or reversing neurovascular injuries in DR are discussed as well.

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Section: Main Textmentioning

confidence: 99%

Neurovascular unit in diabetic retinopathy: pathophysiological roles and potential therapeutical targets

Shen¹,

Lo²,

Mi³

et al. 2021

Eye and Vis

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“…They can be both derived from iPSCs and applied to mimic vascular abnormalities to better understand the molecular mechanisms underlying human diseases. hiPSC-ECs are highly relevant in both disease modeling and therapeutic interventions with their beneficial potential already tested in many preclinical animal studies resembling the conditions associated with hypoxia, such as wound healing [108][109][110][111], hindlimb ischemia [86,[110][111][112][113][114][115][116], retinopathy [117][118][119], and myocardial infarction [120][121][122][123] (Figure 6). In these studies, it was demonstrated that the transplantation of hiPSC-ECs improved the disease condition through either integration into the host vasculature or paracrine activation.…”

Section: Application Of Hipsc-ecs For Ischemia-related Disordersmentioning

confidence: 99%

“…Retinal vascular abnormalities, like diabetic retinopathy and retinal vein occlusion, are associated with retinal ischemia and degeneration, resulting in vision loss. Cell therapy aiming at the restoration of the function of both damaged retinal vasculature and neurons was tested in several studies [117][118][119].…”

Section: Retinopathymentioning

confidence: 99%

Hypoxia as a Driving Force of Pluripotent Stem Cell Reprogramming and Differentiation to Endothelial Cells

et al. 2020

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Inadequate supply of oxygen (O2) is a hallmark of many diseases, in particular those related to the cardiovascular system. On the other hand, tissue hypoxia is an important factor regulating (normal) embryogenesis and differentiation of stem cells at the early stages of embryonic development. In culture, hypoxic conditions may facilitate the derivation of embryonic stem cells (ESCs) and the generation of induced pluripotent stem cells (iPSCs), which may serve as a valuable tool for disease modeling. Endothelial cells (ECs), multifunctional components of vascular structures, may be obtained from iPSCs and subsequently used in various (hypoxia-related) disease models to investigate vascular dysfunctions. Although iPSC-ECs demonstrated functionality in vitro and in vivo, ongoing studies are conducted to increase the efficiency of differentiation and to establish the most productive protocols for the application of patient-derived cells in clinics. In this review, we highlight recent discoveries on the role of hypoxia in the derivation of ESCs and the generation of iPSCs. We also summarize the existing protocols of hypoxia-driven differentiation of iPSCs toward ECs and discuss their possible applications in disease modeling and treatment of hypoxia-related disorders.

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“…[ 139d ] In a recent study by the Duh and Gerecht groups, iPSC‐ECs were able to revascularization the ischemic retina significantly better than human primary endothelial cells, as shown by a higher CXCL12/CXCR4 chemotactic relationship in iPSC‐ECs. [ 140 ] Many groups have also attempted to generate iPSC‐ and ESC‐derived perivascular cells, with many being functionally tested through in vivo implantation in regenerative injury models. [ 139b,141 ] Approaches for recent directed differentiation protocols for pericytes, as well as protocols to mimic endothelial progenitor plasticity, have been summarized by Gerecht and colleagues in 2018.…”

Section: Meso‐ and Microvascular Engineeringmentioning

confidence: 99%

From Arteries to Capillaries: Approaches to Engineering Human Vasculature

Fleischer

Tavakol

Vunjak-Novakovic

2020

Adv Funct Materials

111

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From microscaled capillaries to millimeter‐sized vessels, human vasculature spans multiple scales and cell types. The convergence of bioengineering, materials science, and stem cell biology has enabled tissue engineers to recreate the structure and function of different hierarchical levels of the vascular tree. Engineering large‐scale vessels aims to replace damaged arteries, arterioles, and venules and their routine application in the clinic may become a reality in the near future. Strategies to engineer meso‐ and microvasculature are extensively explored to generate models for studying vascular biology, drug transport, and disease progression as well as for vascularizing engineered tissues for regenerative medicine. However, bioengineering tissues for transplantation has failed to result in clinical translation due to the lack of proper integrated vasculature for effective oxygen and nutrient delivery. The development of strategies to generate multiscale vascular networks and their direct anastomosis to host vasculature would greatly benefit this formidable goal. In this review, design considerations and technologies for engineering millimeter‐, meso‐, and microscale vessels are discussed. Examples of recent state‐of‐the‐art strategies to engineer multiscale vasculature are also provided. Finally, key challenges limiting the translation of vascularized tissues are identified and perspectives on future directions for exploration are presented.

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iPSC-derived endothelial cell response to hypoxia via SDF1a/CXCR4 axis facilitates incorporation to revascularize ischemic retina

Cited by 31 publications

References 27 publications

Neurovascular unit in diabetic retinopathy: pathophysiological roles and potential therapeutical targets

Neurovascular unit in diabetic retinopathy: pathophysiological roles and potential therapeutical targets

Hypoxia as a Driving Force of Pluripotent Stem Cell Reprogramming and Differentiation to Endothelial Cells

From Arteries to Capillaries: Approaches to Engineering Human Vasculature

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