Wharton’s Jelly Mesenchymal Stromal Cells from Human Umbilical Cord: a Close-up on Immunomodulatory Molecules Featured In Situ and In Vitro

Corsello, Tiziana; Amico, Giandomenico; Corrao, Simona; Anzalone, Rita; Timoneri, Francesca; Iacono, Melania Lo; Russo, Eleonora; Spatola, Giovanni Francesco; Uzzo, Maria Laura; Giuffrè, Mario; Čaprnda, Martin; Kubatka, Peter; Kružliak, Peter; Conaldi, Pier Giulio; Rocca, Giampiero La

doi:10.1007/s12015-019-09907-1

Cited by 21 publications

(26 citation statements)

References 49 publications

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“…Our study did not investigate the mechanisms involved in clinical improvement. The suggested role of natural killer cells [ 44 ] and regulatory T cells [ 45 , 46 ] is in line with the mechanism of action of MSC described by other authors [ 47 – 50 ]. Some studies indicated that human neural stem cells transplanted into a spinal cord in patients with ALS differentiated into neurons which were still detected 2.5 years after administration; however, it is not known whether the same happens after administration of MSC [ 51 ].…”

Section: Discussionsupporting

confidence: 75%

Umbilical Cord Mesenchymal Stem Cells in Amyotrophic Lateral Sclerosis: an Original Study

Barczewska

Maksymowicz

Zdolińska-Malinowska

et al. 2020

Stem Cell Rev and Rep

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Objective Amyotrophic lateral sclerosis (ALS) is still incurable. Although different therapies can affect the health and survival of patients. Our aim is to evaluate the effect of umbilical mesenchymal stem cells administrated intrathecally to patients with amyotrophic lateral sclerosis on disability development and survival. Methods This case-control study involved 67 patients treated with Wharton’s jelly mesenchymal stem cells (WJ-MSC). The treated patients were paired with 67 reference patients from the PRO-ACT database which contains patient records from 23 ALS clinical studies (phase 2/3). Patients in the treatment and reference groups were fully matched in terms of race, sex, onset of symptoms (bulbar/spinal), FT9 disease stage at the beginning of therapy and concomitant amyotrophic lateral sclerosis medications. Progression rates prior to treatment varied within a range of ± 0.5 points. All patients received three intrathecal injections of Wharton’s jelly-derived mesenchymal stem cells every two months at a dose of 30 × 10 6 cells. Patients were assessed using the ALSFRS-R scale. Survival times were followed-up until March 2020. Results Median survival time increased two-fold in all groups. In terms of progression, three response types measured in ALSFRS-R were observed: decreased progression rate ( n = 21, 31.3%), no change in progression rate ( n = 33, 49.3%) and increased progression rate ( n = 13, 19.4%). Risk-benefit ratios were favorable in all groups. No serious adverse drug reactions were observed. Interpretation Wharton’s jelly-derived mesenchymal stem cells therapy is safe and effective in some ALS patients, regardless of the clinical features and demographic factors excluding sex. The female sex and a good therapeutic response to the first administration are significant predictors of efficacy following further administrations. Graphical Abstract Medical therapeutic experiment with retrospective case-control analyses Electronic supplementary material The online version of this article (10.1007/s12015-020-10016-7) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 75%

Umbilical Cord Mesenchymal Stem Cells in Amyotrophic Lateral Sclerosis: an Original Study

Barczewska

Maksymowicz

Zdolińska-Malinowska

et al. 2020

Stem Cell Rev and Rep

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“…immunomodulation upon PHA stimulation on PBMNC (46), showing increase in naïve T cells and decrease in memory T cells associated with downregulation of IL-2, IL-12, TNF-a, and IFNγ. More recently IFNγ was identified as principal trigger of PD-L1/PD-1 axis in adipose MSC, significantly contributing to upregulation of different EXO-derived miRNAs involved in immunomodulation (47).…”

Section: Discussionmentioning

confidence: 99%

Integrated Analysis of Transcriptome and Secretome From Umbilical Cord Mesenchymal Stromal Cells Reveal New Mechanisms for the Modulation of Inflammation and Immune Activation

Cruz-Barrera¹,

Flórez-Zapata

Lemus-Diaz

et al. 2020

Front. Immunol.

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Mesenchymal stromal cells (MSC) have been used in over 800 clinical trials with encouraging results in the field of transplant medicine and chronic inflammatory diseases. Today, Umbilical Cord (UC)-derived MSC are the second leading source used for clinical purposes, mainly due to its easy access and superior immune modulatory effects. Although the underlying molecular mechanisms of immune suppressive activities have not been fully understood, research over the last decade strongly suggests that MSC-mediated benefits are closely related to activation of secretome networks. Nevertheless, recent findings also point to cytokine-independent mechanisms as key players of MSC-mediated immune modulation. Here, we set up a robust in vitro immune assay using phytohemagglutinin-or anti-CD3/CD28treated human peripheral blood mononuclear cells in cell-to-cell interaction or in cellcontact independent format with UC-MSC and conducted integrated transcriptome and secretome analyses to dissect molecular pathways driving UC-MSC-mediated immune modulation. Under inflammatory stimuli, multiparametric analyses of the secretome led us to identify cytokine/chemokine expression patterns associated with the induction of MSC-reprogrammed macrophages and T cell subsets ultimately leading to immune suppression. UC-MSC transcriptome analysis under inflammatory challenge allowed the identification of 47 differentially expressed genes, including chemokines, antiand pro-inflammatory cytokines and adhesion molecules found also in UC-MSCimmunosupressive secretomes, including the novel candidate soluble IL-2R. This study enabled us to track functionally activated UC-MSC during immune suppression and opened an opportunity to explore new pathways involved in immunity control by UC-MSC. We propose that identified immunomodulatory molecules and pathways could potentially be translated into clinical settings in order to improve UC-MSC-therapy quality and efficacy.

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“…That MSCs augment mitochondria function may play a key role in sequestering the mitochondrial dysfunction implicated in stroke-induced secondary cell death [29][30][31]. The isolation of potent hUC-MSCs [32][33][34][35][36][37][38][39] towards repairing the mitochondria stands as novel stroke therapy. Cell-based regenerative medicine, which has been demonstrated to be a potent treatment for a number of neurological disorders [39][40][41][42][43][44][45][46], may benefit from transplantation of stem cell-derived mitochondria.…”

Section: Discussionmentioning

confidence: 99%

Energy Metabolism Analysis of Three Different Mesenchymal Stem Cell Populations of Umbilical Cord Under Normal and Pathologic Conditions

Russo

Lee

Nguyen

et al. 2020

Stem Cell Rev and Rep

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Human umbilical cord mesenchymal stem cells (hUC-MSCs) are a pivotal source of therapeutically active cells for regenerative medicine due to their multipotent differentiation potential, immunomodulatory and anti-inflammatory proprieties, as well as logistical collection advantages without ethical concerns. However, it remains poorly understood whether MSCs from different compartments of the human umbilical cord are therapeutically superior than others. In this study, MSCs were isolated from Wharton's jelly (WJ-MSCs), perivascular region (PV-MSCs) and cord lining (CL-MSCs) of hUC. These cells expressed the mesenchymal markers (CD90, CD73), stemness marker (OCT4), endothelial cell adhesion molecular marker (CD146), and the monocyte/macrophage marker (CD14) found within the MSC population implicated as a key regulator of inflammatory responses to hypoxia, was displayed by WJ-, PV-, and CL-MSCs respectively. A direct consequence of oxygen and glucose deprivation during stroke and reperfusion is impaired mitochondrial function that contributes to cellular death. Emerging findings of mitochondria transfer provide the basis for the replenishment of healthy mitochondria as a strategy for the treatment of stroke. Cell Energy Phenotype and Mito Stress tests were performed the energy metabolic profile of the three MSC populations and their mitochondrial function in both ambient and OGD cell culture conditions. PV-MSCs showed the highest mitochondrial activity. CL-MSCs were the least affected by OGD/R condition, suggesting their robust survival in ischemic environment. In this study, MSC populations in UC possess comparable metabolic capacities and good survival under normal and hypoxic conditions suggesting their potential as transplantable cells for mitochondrial-based stem cell therapy in stroke and other ischemic diseases.

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Wharton’s Jelly Mesenchymal Stromal Cells from Human Umbilical Cord: a Close-up on Immunomodulatory Molecules Featured In Situ and In Vitro

Cited by 21 publications

References 49 publications

Umbilical Cord Mesenchymal Stem Cells in Amyotrophic Lateral Sclerosis: an Original Study

Umbilical Cord Mesenchymal Stem Cells in Amyotrophic Lateral Sclerosis: an Original Study

Integrated Analysis of Transcriptome and Secretome From Umbilical Cord Mesenchymal Stromal Cells Reveal New Mechanisms for the Modulation of Inflammation and Immune Activation

Energy Metabolism Analysis of Three Different Mesenchymal Stem Cell Populations of Umbilical Cord Under Normal and Pathologic Conditions

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