Dysregulated Dermal Mesenchymal Stem Cell Proliferation and Differentiation Interfered by Glucose Metabolism in Psoriasis

Zhao, Xincheng; Xing, Jianxiao; Li, Junqin; Hou, Ruixia; Niu, Xuping; Liu, Ruifeng; Jiao, Juan-Juan; Yang, Xiaohong; Li, Juan; Liang, Jiannan; Zhou, Ling; Wang, Qiang; Chang, Wenjuan; Yin, Guohua; Li, Xinhua; Zhang, Kaiming

doi:10.15283/ijsc20073

Cited by 6 publications

(4 citation statements)

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“…An upregulation of GLUT1 and HK2 has also been found in dermal PsO-MSCs [ 25 ]. OCR (oxygen consumption rate), ATP-linked respiration, maximal respiration, and reserve capacity are significantly higher in PsO-MSCs than in Control-MSCs C/MSCs.…”

Section: Resultsmentioning

confidence: 99%

“…Vascular hyperplasia is evident in psoriatic lesions. It was shown that the number of blood vessels in the psoriatic skin significantly increased compared to the control group [ 25 ]. Overexpression of pro-angiogenic mediators such as VEGF, IGFBP-5, DEL-1, and angiopoietin-2 in dermal PsO-MSCs has been consolidated [ 14 , 26 , 27 ] ( Figure 3 ).…”

Section: Resultsmentioning

confidence: 99%

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Mesenchymal Stem Cells and Psoriasis: Systematic Review

Diotallevi

Vincenzo

Martina

et al. 2022

IJMS

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Mesenchymal Stem Cells (MSCs) are multipotent non-hematopoietic stromal cells found in different body tissues such as bone marrow, adipose tissue, periosteum, Wharton’s jelly, umbilical cord, blood, placenta, amniotic fluid, and skin. The biological behavior of MSCs depends mainly on their interaction with the microenvironment in which they are found, whose quality deeply influences the regenerative and immunomodulatory properties of these cells. Several studies confirm the interaction between MSCs and inflammatory microenvironment in the pathogenesis of psoriasis, designating MSCs as an important factor driving psoriasis development. This review aims to describe the most recent evidence on how the inflammatory microenvironment that characterizes psoriasis influences the homeostasis of MSCs and how they can be used to treat the disease.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Mesenchymal Stem Cells and Psoriasis: Systematic Review

Diotallevi

Vincenzo

Martina

et al. 2022

IJMS

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“…The Warburg effect, or aerobic glycolysis, is a well-studied process of metabolic redirection that supports the energetic and anabolic requirements of proliferating cells, including psoriatic keratinocytes. Recent studies have reported a significant upregulation of glucose transporter 1 (GLUT1) and key glycolytic enzymes such as phosphoglycerate mutase 1 (PGAM1) and pyruvate kinase 2 (PKM2) in psoriatic epidermal keratinocytes (Zhang et al, 2018;Liu et al, 2021;Zhao et al, 2021). Moreover, pharmacological inhibition or genetic knockout of these glycolytic genes has been shown to arrest keratinocyte proliferation and reduce inflammatory responses effectively (Zhang et al, 2018;Liu et al, 2021;Kim et al, 2022).…”

Section: Introductionmentioning

confidence: 99%

Deciphering the mechanism of PSORI-CM02 in suppressing keratinocyte proliferation through the mTOR/HK2/glycolysis axis

et al. 2023

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Hyperplasia of epidermal keratinocytes that depend on glycolysis is a new hallmark of psoriasis pathogenesis. Our previous studies demonstrated that PSORI-CM02 could halt the pathological progression of psoriasis by targeting inflammatory response and angiogenesis, but its effect(s) and mechanism(s) on proliferating keratinocytes remained unclear. In this study, we aim to identify components of PSORI-CM02 that are absorbed into the blood and to determine the effect(s) of PSORI-CM02 on keratinocyte proliferation and its molecular mechanism(s). We used the immortalized human epidermal keratinocyte cell line, HaCaT, as an in vitro model of proliferating keratinocytes and the imiquimod-induced psoriasis mouse (IMQ) as an in vivo model. Metabolite profiles of vehicle pharmaceutic serum (VPS), PSORI-CM02 pharmaceutic serum (PPS), and water extraction (PWE) were compared, and 23 components of PSORI-CM02 were identified that were absorbed into the blood of mice. Both PPS and PWE inhibited the proliferation of HaCaT cells and consequently reduced the expression of the proliferation marker ki67. Additionally, PPS and PWE reduced phosphorylation levels of mTOR pathway kinases. Seahorse experiments demonstrated that PPS significantly inhibited glycolysis, glycolytic capacity, and mitochondrial respiration, thus reducing ATP production in HaCaT cells. Upon treatments of PPS or PWE, hexokinase 2 (HK2) expression was significantly decreased, as observed from the set of glycolytic genes we screened. Finally, in the IMQ model, we observed that treatment with PSORI-CM02 or BPTES, an inhibitor of mTOR signaling, reduced hyperproliferation of epidermal keratinocytes, inhibited the expression of p-S6 and reduced the number of proliferating cell nuclear antigen (PCNA)-positive cells in lesioned skin. Taken together, we demonstrate that PSORI-CM02 has an anti-proliferative effect on psoriatic keratinocytes, at least in part, by inhibiting the mTOR/HK2/glycolysis axis.

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“…The Warburg effect, or aerobic glycolysis, is a well-studied process of metabolic redirection that supports the energetic and anabolic requirements of proliferating cells, including psoriatic keratinocytes. Recent studies have reported a significant upregulation of glucose transporter 1 (GLUT1) and key glycolytic enzymes such as phosphoglycerate mutase 1 (PGAM1) and pyruvate kinase 2 (PKM2) in psoriatic epidermal keratinocytes Zhao et al, 2021). Moreover, pharmacological inhibition or genetic knockout of these glycolytic genes has been shown to arrest keratinocyte proliferation and reduce inflammatory responses effectively (Kim et al, 2022;.…”

Section: Discussionmentioning

confidence: 99%

Metabolic crosstalk between keratinocytes and immune cells: new therapeutic options for psoriasis treatment

Wang

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Psoriasis is a complex autoimmune disease characterized by dysregulated interactions between keratinocytes and immune cells. Over the past decade, various antimicrobial peptides, chemokines, and cytokines have been discovered as key mediators in the interplay between keratinocytes and immune cells. These discoveries contribute to the development and application of biologics in the treatment of psoriasis patients. The thickened skin lesions in psoriasis likely represent a resource-limited microenvironment and, how different cells manage resource allocation is a critical question. Hence, different cells need to reprogram their metabolic patterns and establish beneficial metabolic crosstalk to coexist. However, our understanding of the metabolic reprogramming of keratinocytes and their metabolic crosstalk with other cell types in psoriasis is still limited. To address these issues, in Chapters 2 and 3, we first studied the miR-31-induced metabolic reprogramming in keratinocytes, which was found to enhance glutamine metabolism and promote the secretion of immune molecules and metabolites. The composition of these secreted substances facilitate the differentiation of CD4+ naïve T cells into Th17 cells. Especially, aspartate was found to enhance Th17 cell differentiation induced by IL-6 and TGFβ, by upregulating glycolysis to sustain the malate aspartate shuttle (MAS) and increase oxidative phosphorylation of Th17 cells. Subsequent in vitro and in vivo experiments demonstrated that targeting GLS (inhibiting glutaminolysis), SLC1A3 (blocking aspartate uptake), or GOT1 (inhibiting aspartate metabolism) can reduce Th17 cell differentiation and alleviated skin inflammation in a mouse model of psoriasis. Notably, aspartate was found elevated in the serum of psoriasis patients. In addition, the psoriasis-derived CD4+ naïve T cells expressed high levels of GOT1 and MDH1 and increased the aspartate and glutamate metabolism pathway as compared to those from healthy subjects. Collectively, our in vitro and in vivo results demonstrate that highly expressed miR-31 in keratinocytes can influence the local and systemic metabolic environment and build metabolic crosstalk with immune cells to amplify the inflammatory feedback loop in psoriasis. In Chapter 4, we demonstrate that the metabolites in the serum of psoriasis patients mediate crosstalk between different types of immune cells upon treatment with Methotrexate. These findings highlight the pervasive presence of metabolic crosstalk and its significant contribution to the therapeutic effects of methotrexate in treating psoriasis. In Chapter 5, we show that PSORI-CM02, a Chinese herbal formula that is used clinically in the treatment of psoriasis, effectively reduced HK2 expression and attenuated glycolysis in keratinocytes through the mTOR pathway. In conclusion, we uncovered the metabolic reprogramming of psoriasis keratinocytes and their metabolic crosstalk with CD4+ naïve T cells. We also provided initial insights into the therapeutic potential of targeting either the glutamine-dependent differentiated keratinocytes or the glucose-dependent proliferating keratinocytes, as well as blocking the aspartate-dependent metabolic crosstalk between keratinocytes and CD4+ naïve T cells. These studies have expanded our understanding of the interaction mechanisms between keratinocytes and immune cells, introducing metabolites such as aspartate as novel mediators and offering new strategies for the treatment of psoriasis.

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Dysregulated Dermal Mesenchymal Stem Cell Proliferation and Differentiation Interfered by Glucose Metabolism in Psoriasis

Cited by 6 publications

References 40 publications

Mesenchymal Stem Cells and Psoriasis: Systematic Review

Mesenchymal Stem Cells and Psoriasis: Systematic Review

Deciphering the mechanism of PSORI-CM02 in suppressing keratinocyte proliferation through the mTOR/HK2/glycolysis axis

Metabolic crosstalk between keratinocytes and immune cells: new therapeutic options for psoriasis treatment

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