Deletion of STAT3 from Foxd1 cell population protects mice from kidney fibrosis by inhibiting pericytes trans-differentiation and migration

Ajay, Amrendra K.; Zhao, Li; Vig, Shruti; Fujiwara, Mai; Thakurela, Sudhir; Jadhav, Shreyas; Cho, Andrew; Chiu, I‐Jen; Ding, Yan; Ramachandran, Krithika; Mithal, Arushi; Bhatt, Aanal; Chaluvadi, Pratyusha; Gupta, Manoj Kumar; Shah, Sujal I.; Sabbisetti, Venkata; Waaga-Gasser, Ana Maria; Frank, David A.; Murugaiyan, Gopal; Bonventre, Joseph V.; Hsiao, Li‐Li

doi:10.1016/j.celrep.2022.110473

Cited by 29 publications

(16 citation statements)

References 92 publications

(116 reference statements)

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“…Brain pericytes modulate neuroinflammation by regulating immune cell recruitment and activation ( 39 , 41 , 42 , 44 , 57 , 58 ). Kidney pericytes secrete cytokines in response to tissue damage ( 40 , 43 ). Pericytes may also contribute to pathologies through immune cell activation.…”

Section: Discussionmentioning

confidence: 99%

“…Further, this activity can be mediated by secreted factors, including NGF, BMP4, and ECM components, independently of blood flow regulation (32,(34)(35)(36)(37). Studies suggest that pericytes may have an immunoregulatory role in various tissues, including the brain and kidneys, by secreting cytokines to control immune cell infiltration and activation (39)(40)(41)(42)(43)(44). However, whether pericytes in the islets also have this function has yet to be determined.…”

Section: Introductionmentioning

confidence: 99%

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Pericytes modulate islet immune cells and insulin secretion through Interleukin-33 production in mice

et al. 2023

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IntroductionImmune cells were recently shown to support β-cells and insulin secretion. However, little is known about how islet immune cells are regulated to maintain glucose homeostasis. Administration of various cytokines, including Interleukin-33 (IL-33), was shown to influence β-cell function. However, the role of endogenous, locally produced IL-33 in pancreatic function remains unknown. Here, we show that IL-33, produced by pancreatic pericytes, is required for glucose homeostasis.MethodsTo characterize pancreatic IL-33 production, we employed gene expression, flow cytometry, and immunofluorescence analyses. To define the role of this cytokine, we employed transgenic mouse systems to delete the Il33 gene selectively in pancreatic pericytes, in combination with the administration of recombinant IL-33. Glucose response was measured in vivo and in vitro, and morphometric and molecular analyses were used to measure β-cell mass and gene expression. Immune cells were analyzed by flow cytometry.ResutsOur results show that pericytes are the primary source of IL-33 in the pancreas. Mice lacking pericytic IL-33 were glucose intolerant due to impaired insulin secretion. Selective loss of pericytic IL-33 was further associated with reduced T and dendritic cell numbers in the islets and lower retinoic acid production by islet macrophages.DiscussionOur study demonstrates the importance of local, pericytic IL-33 production for glucose regulation. Additionally, it proposes that pericytes regulate islet immune cells to support β-cell function in an IL-33-dependent manner. Our study reveals an intricate cellular network within the islet niche.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Pericytes modulate islet immune cells and insulin secretion through Interleukin-33 production in mice

et al. 2023

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“…Accordingly, regenerative therapies using exogenous pericytes have been preclinically tested (31)(32)(33)(34)(35)(36)(37). Pericytes were delivered either as dispersed preparations or as a part of a "tissue-engineered" product to models of myocardial infarction (MI) (33,36,37), congenital heart disease (34,35), limb ischemia (38), muscular dystrophy and skeletal muscle injuries (39)(40)(41)(42), blood-brain barrier disorders (43)(44)(45)(46)(47)(48), diabetic retinopathy (49)(50)(51), and kidney fibrosis (52). These preclinical studies have paved the way for future therapeutic applications in human diseases.…”

Section: Functional Roles Of Pericytesmentioning

confidence: 99%

“…The final population is highly pure for the selected antigens, but cell yields may be insufficient for immediate applications requiring large cell quantities. The strategy for gating cells can make a profound difference in the outcomes ( 12 , 39 , 41 , 42 , 44 , 52 , 90 , 104 , 105 ).…”

Section: Current Protocols For the Derivation Of Pericyte Populationsmentioning

confidence: 99%

Approaches for the isolation and long-term expansion of pericytes from human and animal tissues

Alvino

Mohammed

et al. 2023

Front. Cardiovasc. Med.

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Pericytes surround capillaries in every organ of the human body. They are also present around the vasa vasorum, the small blood vessels that supply the walls of larger arteries and veins. The clinical interest in pericytes is rapidly growing, with the recognition of their crucial roles in controlling vascular function and possible therapeutic applications in regenerative medicine. Nonetheless, discrepancies in methods used to define, isolate, and expand pericytes are common and may affect reproducibility. Separating pure pericyte preparations from the continuum of perivascular mesenchymal cells is challenging. Moreover, variations in functional behavior and antigenic phenotype in response to environmental stimuli make it difficult to formulate an unequivocal definition of bona fide pericytes. Very few attempts were made to develop pericytes as a clinical-grade product. Therefore, this review is devoted to appraising current methodologies’ pros and cons and proposing standardization and harmonization improvements. We highlight the importance of developing upgraded protocols to create therapeutic pericyte products according to the regulatory guidelines for clinical manufacturing. Finally, we describe how integrating RNA-seq techniques with single-cell spatial analysis, and functional assays may help realize the full potential of pericytes in health, disease, and tissue repair.

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“…Conversely, adult kidneys have some capacity of endogenous cellular replacement and remodelling that restores renal structure and function following acute kidney damage, which is predominantly achieved by dedifferentiation and migration of the surviving tubular epithelial cells from the site of apoptosis and cell detachment post-injury, where they proliferate and re-differentiate into functional tubular epithelial cells [ 33 , 34 , 35 ]. However, previous studies have suggested a relatively small con-tribution of Foxd1 stromal cells and other resident stem cells in the regeneration and re-modelling of newly viable tubular cells [ 34 , 36 , 37 ]. Over the last couple of decades, the field of regenerative medicine has emerged as a novel promising strategy to modulate the disease progression of CKD.…”

Section: Mesenchymal-stem-cell-based Therapymentioning

confidence: 99%

Enhancing the Therapeutic Potential of Mesenchymal Stromal Cell-Based Therapies with an Anti-Fibrotic Agent for the Treatment of Chronic Kidney Disease

Ricardo

Samuel

2022

IJMS

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Chronic kidney disease (CKD) affects 1 in 10 members of the general population, placing these patients at an increasingly high risk of kidney failure. Despite the significant burden of CKD on various healthcare systems, there are no effective cures that reverse or even halt its progression. In recent years, human bone-marrow-derived mesenchymal stromal cells (BM-MSCs) have been recognised as a novel therapy for CKDs, owing to their well-established immunomodulatory and tissue-reparative properties in preclinical settings, and their promising safety profile that has been demonstrated in patients with CKDs from several clinical trials. However, renal fibrosis (scarring), a hallmark of CKD, has been shown to impair the viability and functionality of BM-MSCs post-transplantation. This has suggested that BM-MSCs might require a pre-treatment or adjunct therapy that can enhance the viability and therapeutic efficacy of these stromal cells in chronic disease settings. To address this, recent studies that have combined BM-MSCs with the anti-fibrotic drug serelaxin (RLX), have demonstrated the enhanced therapeutic potential of this combination therapy in normotensive and hypertensive preclinical models of CKD. In this review, a critical appraisal of the preclinical data available on the anti-fibrotic and renoprotective actions of BM-MSCs or RLX alone and when combined, as a treatment option for normotensive vs. hypertensive CKD, is discussed.

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Deletion of STAT3 from Foxd1 cell population protects mice from kidney fibrosis by inhibiting pericytes trans-differentiation and migration

Cited by 29 publications

References 92 publications

Pericytes modulate islet immune cells and insulin secretion through Interleukin-33 production in mice

Pericytes modulate islet immune cells and insulin secretion through Interleukin-33 production in mice

Approaches for the isolation and long-term expansion of pericytes from human and animal tissues

Enhancing the Therapeutic Potential of Mesenchymal Stromal Cell-Based Therapies with an Anti-Fibrotic Agent for the Treatment of Chronic Kidney Disease

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