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3 pages, 186 KiB

Open AccessEditorial

Stem Cells to the Rescue: Development and Application of Cell-Based Therapy for Microvascular Repair

by Lilach O. Lerman and Amir Lerman

Cells 2021, 10(8), 2144; https://doi.org/10.3390/cells10082144 - 20 Aug 2021

Viewed by 1538

Abstract

The microcirculation includes an invisible network of micro-vessels that are up to a few hundred microns in diameter [...] Full article

(This article belongs to the Special Issue Stem Cells to the Rescue: Development and Application of Cell-Based Therapy for Microvascular Repair)

Research

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15 pages, 1569 KiB

Open AccessArticle

Stem Cell Therapy for Microvascular Injury Associated with Ischemic Nephropathy

by Stephen C. Textor, Abdu Abumoawad, Ahmed Saad, Christopher Ferguson and Allan Dietz

Cells 2021, 10(4), 765; https://doi.org/10.3390/cells10040765 - 31 Mar 2021

Cited by 6 | Viewed by 2732

Abstract

Ischemic nephropathy reflects progressive loss of kidney function due to large vessel atherosclerotic occlusive disease. Recent studies indicate that this process is characterized by microvascular rarefaction, increased tissue hypoxia and activation of inflammatory processes of tissue injury. This review summarizes the rationale and [...] Read more.

Ischemic nephropathy reflects progressive loss of kidney function due to large vessel atherosclerotic occlusive disease. Recent studies indicate that this process is characterized by microvascular rarefaction, increased tissue hypoxia and activation of inflammatory processes of tissue injury. This review summarizes the rationale and application of functional MR imaging to evaluate tissue oxygenation in human subjects that defines the limits of renal adaptation to reduction in blood flow, development of increasingly severe tissue hypoxia and recruitment of inflammatory injury pathways in ischemic nephropathy. Human mesenchymal stromal/stem cells (MSC) are capable of modifying angiogenic pathways and immune responses, but the potency of these effects vary between individuals and various clinical characteristics including age and chronic kidney disease and levels of hypoxia. We summarize recently completed first-in-human studies applying intrarenal infusion of autologous adipose-derived MSC in human subjects with ischemic nephropathy that demonstrate a rise in blood flow and reduction in tissue hypoxia consistent with partial repair of microvascular injury, even without restoring main renal arterial blood flow. Inflammatory biomarkers in the renal vein of post-stenotic kidneys fell after MSC infusion. These changes were associated with modest but significant dose-related increments in kidney function. These data provide support a role for autologous MSC in repair of microvascular injury associated with tissue hypoxia. Full article

(This article belongs to the Special Issue Stem Cells to the Rescue: Development and Application of Cell-Based Therapy for Microvascular Repair)

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16 pages, 11807 KiB

Open AccessArticle

Mesenchymal Stem/Stromal Cell-Derived Extracellular Vesicles Elicit Better Preservation of the Intra-Renal Microvasculature Than Renal Revascularization in Pigs with Renovascular Disease

by Christopher M. Ferguson, Rahele A. Farahani, Xiang-Yang Zhu, Hui Tang, Kyra L. Jordan, Ishran M. Saadiq, Amir Lerman, Lilach O. Lerman and Alfonso Eirin

Cells 2021, 10(4), 763; https://doi.org/10.3390/cells10040763 - 31 Mar 2021

Cited by 9 | Viewed by 2399

Abstract

Background: Percutaneous transluminal renal angioplasty (PTRA) confers clinical and mortality benefits in select ‘high-risk’ patients with renovascular disease (RVD). Intra-renal-delivered extracellular vesicles (EVs) released from mesenchymal stem/stromal cells (MSCs) protect the kidney in experimental RVD, but have not been compared side-by-side to clinically [...] Read more.

Background: Percutaneous transluminal renal angioplasty (PTRA) confers clinical and mortality benefits in select ‘high-risk’ patients with renovascular disease (RVD). Intra-renal-delivered extracellular vesicles (EVs) released from mesenchymal stem/stromal cells (MSCs) protect the kidney in experimental RVD, but have not been compared side-by-side to clinically applied interventions, such as PTRA. We hypothesized that MSC-derived EVs can comparably protect the post-stenotic kidney via direct tissue effects. Methods: Five groups of pigs (n = 6 each) were studied after 16 weeks of RVD, RVD treated 4 weeks earlier with either PTRA or MSC-derived EVs, and normal controls. Single-kidney renal blood flow (RBF) and glomerular filtration rate (GFR) were assessed in vivo with multi-detector CT, and renal microvascular architecture (3D micro CT) and injury pathways ex vivo. Results: Despite sustained hypertension, EVs conferred greater improvement of intra-renal microvascular and peritubular capillary density compared to PTRA, associated with attenuation of renal inflammation, oxidative stress, and tubulo-interstitial fibrosis. Nevertheless, stenotic kidney RBF and GFR similarly rose in both PTRA- and EV-treated pigs compared RVD + Sham. mRNA sequencing reveled that EVs were enriched with pro-angiogenic, anti-inflammatory, and antioxidants genes. Conclusion: MSC-derived EVs elicit a better preservation of the stenotic kidney microvasculature and greater attenuation of renal injury and fibrosis compared to PTRA, possibly partly attributed to their cargo of vasculo-protective genes. Yet, both strategies similarly improve renal hemodynamics and function. These observations shed light on diverse mechanisms implicated in improvement of post-stenotic kidney function and position EVs as a promising therapeutic intervention in RVD. Full article

(This article belongs to the Special Issue Stem Cells to the Rescue: Development and Application of Cell-Based Therapy for Microvascular Repair)

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18 pages, 8506 KiB

Open AccessArticle

Concentrated Secretome of Adipose Stromal Cells Limits Influenza A Virus-Induced Lung Injury in Mice

by Natalia V. Bogatcheva and Michael E. Coleman

Cells 2021, 10(4), 720; https://doi.org/10.3390/cells10040720 - 24 Mar 2021

Cited by 6 | Viewed by 2515

Abstract

Despite vaccination and antivirals, influenza remains a communicable disease of high burden, with limited therapeutic options available to patients that develop complications. Here, we report the development and preclinical characterization of Adipose Stromal Cell (ASC) concentrated secretome (CS), generated by process adaptable to [...] Read more.

Despite vaccination and antivirals, influenza remains a communicable disease of high burden, with limited therapeutic options available to patients that develop complications. Here, we report the development and preclinical characterization of Adipose Stromal Cell (ASC) concentrated secretome (CS), generated by process adaptable to current Good Manufacturing Practices (cGMP) standards. We demonstrate that ASC-CS limits pulmonary histopathological changes, infiltration of inflammatory cells, protein leak, water accumulation, and arterial oxygen saturation (spO2) reduction in murine model of lung infection with influenza A virus (IAV) when first administered six days post-infection. The ability to limit lung injury is sustained in ASC-CS preparations stored at −80 °C for three years. Priming of the ASC with inflammatory factors TNFα and IFNγ enhances ASC-CS ability to suppress lung injury. IAV infection is associated with dramatic increases in programmed cell death ligand (PDL1) and angiopoietin 2 (Angpt2) levels. ASC-CS application significantly reduces both PDL1 and Angpt2 levels. Neutralization of PDL1 with anti-mouse PDL1 antibody starting Day6 onward effectively ablates lung PDL1, but only non-significantly reduces Angpt2 release. Most importantly, late-phase PDL1 neutralization results in negligible suppression of protein leakage and inflammatory cell infiltration, suggesting that suppression of PDL1 does not play a critical role in ASC-CS therapeutic effects. Full article

(This article belongs to the Special Issue Stem Cells to the Rescue: Development and Application of Cell-Based Therapy for Microvascular Repair)

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Review

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16 pages, 1617 KiB

Open AccessFeature PaperReview

Angiogenic CD34 Stem Cell Therapy in Coronary Microvascular Repair—A Systematic Review

by Balaj Rai, Janki Shukla, Timothy D. Henry and Odayme Quesada

Cells 2021, 10(5), 1137; https://doi.org/10.3390/cells10051137 - 8 May 2021

Cited by 12 | Viewed by 4383

Abstract

Ischemia with non-obstructive coronary arteries (INOCA) is an increasingly recognized disease, with a prevalence of 3 to 4 million individuals, and is associated with a higher risk of morbidity, mortality, and a worse quality of life. Persistent angina in many patients with INOCA [...] Read more.

Ischemia with non-obstructive coronary arteries (INOCA) is an increasingly recognized disease, with a prevalence of 3 to 4 million individuals, and is associated with a higher risk of morbidity, mortality, and a worse quality of life. Persistent angina in many patients with INOCA is due to coronary microvascular dysfunction (CMD), which can be difficult to diagnose and treat. A coronary flow reserve <2.5 is used to diagnose endothelial-independent CMD. Antianginal treatments are often ineffective in endothelial-independent CMD and thus novel treatment modalities are currently being studied for safety and efficacy. CD34⁺ cell therapy is a promising treatment option for these patients, as it has been shown to promote vascular repair and enhance angiogenesis in the microvasculature. The resulting restoration of the microcirculation improves myocardial tissue perfusion, resulting in the recovery of coronary microvascular function, as evidenced by an improvement in coronary flow reserve. A pilot study in INOCA patients with endothelial-independent CMD and persistent angina, treated with autologous intracoronary CD34⁺ stem cells, demonstrated a significant improvement in coronary flow reserve, angina frequency, Canadian Cardiovascular Society class, and quality of life (ESCaPE-CMD, NCT03508609). This work is being further evaluated in the ongoing FREEDOM (NCT04614467) placebo-controlled trial. Full article

(This article belongs to the Special Issue Stem Cells to the Rescue: Development and Application of Cell-Based Therapy for Microvascular Repair)

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12 pages, 11030 KiB

Open AccessFeature PaperReview

Mixing Cells for Vascularized Kidney Regeneration

by Michael Namestnikov, Oren Pleniceanu and Benjamin Dekel

Cells 2021, 10(5), 1119; https://doi.org/10.3390/cells10051119 - 6 May 2021

Cited by 5 | Viewed by 3529

Abstract

The worldwide rise in prevalence of chronic kidney disease (CKD) demands innovative bio-medical solutions for millions of kidney patients. Kidney regenerative medicine aims to replenish tissue which is lost due to a common pathological pathway of fibrosis/inflammation and rejuvenate remaining tissue to maintain [...] Read more.

The worldwide rise in prevalence of chronic kidney disease (CKD) demands innovative bio-medical solutions for millions of kidney patients. Kidney regenerative medicine aims to replenish tissue which is lost due to a common pathological pathway of fibrosis/inflammation and rejuvenate remaining tissue to maintain sufficient kidney function. To this end, cellular therapy strategies devised so far utilize kidney tissue-forming cells (KTFCs) from various cell sources, fetal, adult, and pluripotent stem-cells (PSCs). However, to increase engraftment and potency of the transplanted cells in a harsh hypoxic diseased environment, it is of importance to co-transplant KTFCs with vessel forming cells (VFCs). VFCs, consisting of endothelial cells (ECs) and mesenchymal stem-cells (MSCs), synergize to generate stable blood vessels, facilitating the vascularization of self-organizing KTFCs into renovascular units. In this paper, we review the different sources of KTFCs and VFCs which can be mixed, and report recent advances made in the field of kidney regeneration with emphasis on generation of vascularized kidney tissue by cell transplantation. Full article

(This article belongs to the Special Issue Stem Cells to the Rescue: Development and Application of Cell-Based Therapy for Microvascular Repair)

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22 pages, 3653 KiB

Open AccessReview

Imaging the Renal Microcirculation in Cell Therapy

by Katerina Apelt, Roel Bijkerk, Franck Lebrin and Ton J. Rabelink

Cells 2021, 10(5), 1087; https://doi.org/10.3390/cells10051087 - 2 May 2021

Cited by 6 | Viewed by 12549

Abstract

Renal microvascular rarefaction plays a pivotal role in progressive kidney disease. Therefore, modalities to visualize the microcirculation of the kidney will increase our understanding of disease mechanisms and consequently may provide new approaches for evaluating cell-based therapy. At the moment, however, clinical practice [...] Read more.

Renal microvascular rarefaction plays a pivotal role in progressive kidney disease. Therefore, modalities to visualize the microcirculation of the kidney will increase our understanding of disease mechanisms and consequently may provide new approaches for evaluating cell-based therapy. At the moment, however, clinical practice is lacking non-invasive, safe, and efficient imaging modalities to monitor renal microvascular changes over time in patients suffering from renal disease. To emphasize the importance, we summarize current knowledge of the renal microcirculation and discussed the involvement in progressive kidney disease. Moreover, an overview of available imaging techniques to uncover renal microvascular morphology, function, and behavior is presented with the associated benefits and limitations. Ultimately, the necessity to assess and investigate renal disease based on in vivo readouts with a resolution up to capillary level may provide a paradigm shift for diagnosis and therapy in the field of nephrology. Full article

(This article belongs to the Special Issue Stem Cells to the Rescue: Development and Application of Cell-Based Therapy for Microvascular Repair)

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24 pages, 1512 KiB

Open AccessReview

Mesenchymal Stem Cell Derived Extracellular Vesicles for Repairing the Neurovascular Unit after Ischemic Stroke

by Courtney Davis, Sean I. Savitz and Nikunj Satani

Cells 2021, 10(4), 767; https://doi.org/10.3390/cells10040767 - 31 Mar 2021

Cited by 25 | Viewed by 4076

Abstract

Ischemic stroke is a debilitating disease and one of the leading causes of long-term disability. During the early phase after ischemic stroke, the blood-brain barrier (BBB) exhibits increased permeability and disruption, leading to an influx of immune cells and inflammatory molecules that exacerbate [...] Read more.

Ischemic stroke is a debilitating disease and one of the leading causes of long-term disability. During the early phase after ischemic stroke, the blood-brain barrier (BBB) exhibits increased permeability and disruption, leading to an influx of immune cells and inflammatory molecules that exacerbate the damage to the brain tissue. Mesenchymal stem cells have been investigated as a promising therapy to improve the recovery after ischemic stroke. The therapeutic effects imparted by MSCs are mostly paracrine. Recently, the role of extracellular vesicles released by these MSCs have been studied as possible carriers of information to the brain. This review focuses on the potential of MSC derived EVs to repair the components of the neurovascular unit (NVU) controlling the BBB, in order to promote overall recovery from stroke. Here, we review the techniques for increasing the effectiveness of MSC-based therapeutics, such as improved homing capabilities, bioengineering protein expression, modified culture conditions, and customizing the contents of EVs. Combining multiple techniques targeting NVU repair may provide the basis for improved future stroke treatment paradigms. Full article

(This article belongs to the Special Issue Stem Cells to the Rescue: Development and Application of Cell-Based Therapy for Microvascular Repair)

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25 pages, 1176 KiB

Open AccessReview

Stem Cells in Cardiovascular Diseases: 30,000-Foot View

by Thomas J. Povsic and Bernard J. Gersh

Cells 2021, 10(3), 600; https://doi.org/10.3390/cells10030600 - 9 Mar 2021

Cited by 7 | Viewed by 2730

Abstract

Stem cell and regenerative approaches that might rejuvenate the heart have immense intuitive appeal for the public and scientific communities. Hopes were fueled by initial findings from preclinical models that suggested that easily obtained bone marrow cells might have significant reparative capabilities; however, [...] Read more.

Stem cell and regenerative approaches that might rejuvenate the heart have immense intuitive appeal for the public and scientific communities. Hopes were fueled by initial findings from preclinical models that suggested that easily obtained bone marrow cells might have significant reparative capabilities; however, after initial encouraging pre-clinical and early clinical findings, the realities of clinical development have placed a damper on the field. Clinical trials were often designed to detect exceptionally large treatment effects with modest patient numbers with subsequent disappointing results. First generation approaches were likely overly simplistic and relied on a relatively primitive understanding of regenerative mechanisms and capabilities. Nonetheless, the field continues to move forward and novel cell derivatives, platforms, and cell/device combinations, coupled with a better understanding of the mechanisms that lead to regenerative capabilities in more primitive models and modifications in clinical trial design suggest a brighter future. Full article

(This article belongs to the Special Issue Stem Cells to the Rescue: Development and Application of Cell-Based Therapy for Microvascular Repair)

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22 pages, 375 KiB

Open AccessReview

Stem Cell Repair of the Microvascular Damage in Stroke

by Madeline Saft, Bella Gonzales-Portillo, You Jeong Park, Blaise Cozene, Nadia Sadanandan, Justin Cho, Svitlana Garbuzova-Davis and Cesar V. Borlongan

Cells 2020, 9(9), 2075; https://doi.org/10.3390/cells9092075 - 11 Sep 2020

Cited by 11 | Viewed by 3282

Abstract

Stroke is a life-threatening disease that leads to mortality, with survivors subjected to long-term disability. Microvascular damage is implicated as a key pathological feature, as well as a therapeutic target for stroke. In this review, we present evidence detailing subacute diaschisis in a [...] Read more.

Stroke is a life-threatening disease that leads to mortality, with survivors subjected to long-term disability. Microvascular damage is implicated as a key pathological feature, as well as a therapeutic target for stroke. In this review, we present evidence detailing subacute diaschisis in a focal ischemic stroke rat model with a focus on blood–brain barrier (BBB) integrity and related pathogenic processes in contralateral brain areas. Additionally, we discuss BBB competence in chronic diaschisis in a similar rat stroke model, highlighting the pathological changes in contralateral brain areas that indicate progressive morphological brain disturbances overtime after stroke onset. With diaschisis closely approximating stroke onset and progression, it stands as a treatment of interest for stroke. Indeed, the use of stem cell transplantation for the repair of microvascular damage has been investigated, demonstrating that bone marrow stem cells intravenously transplanted into rats 48 h post-stroke survive and integrate into the microvasculature. Ultrastructural analysis of transplanted stroke brains reveals that microvessels display a near-normal morphology of endothelial cells and their mitochondria. Cell-based therapeutics represent a new mechanism in BBB and microvascular repair for stroke. Full article

(This article belongs to the Special Issue Stem Cells to the Rescue: Development and Application of Cell-Based Therapy for Microvascular Repair)

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