Placenta-derived mesenchymal stem cells possess better immunoregulatory properties compared to their cord-derived counterparts–a paired sample study

Talwadekar, Manasi; Kale, Vaijayanti; Limaye, Lalita

doi:10.1038/srep15784

Cited by 76 publications

(73 citation statements)

References 42 publications

(51 reference statements)

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“…Perhaps the only way to produce the large-scale cell banks required for cellular therapy while minimizing the number of cell-doublings is to start with a large number of unpassaged MSC. This could be accomplished several ways, including pooling cells isolated from an alternative source, such as placenta (48), or using an MSC-rich tissue like adipose, that can be harvested in bulk from living donors (49). Our preferred solution is to isolate bone marrow MSC from cadaveric bone.…”

Section: Discussionmentioning

confidence: 99%

Proteomic Profiling of Native Unpassaged and Culture‐Expanded Mesenchymal Stromal Cells (MSC)

et al. 2018

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Human culture-expanded mesenchymal stromal cells (MSC) are being considered for multiple therapeutic applications because of their regenerative and anti-inflammatory properties. Although a large number of MSC can be propagated from a small initial sample, several lines of evidence indicate that MSC lose their immunosuppressive and regenerative potency aftaer multiple passages. In this report, we use the FACSCAP Lyoplate proteomic analysis system to detect changes in cell surface protein expression of CD45 /CD31 /CD34 /CD73 /CD105 stromal cells in unpassaged bone marrow (BM) and through 10 serial culture passages. We provide for the first time a detailed characterization of native unpassaged BM MSC (0.08% of BM mononuclear cells) as well as the changes that occur during the initial expansion. Adipogenic and osteogenic differentiative potential was determined though the serial passages and correlated with immunophenotypic changes and senescence. Among the most prominent were striking decreases in Fas ligand, CD98, CD205, and CD106, accompanied by a gain in the expression of CD49c, CD63, CD98, and class 1 and class 2 major histocompatibility complex (MHC) molecules. Other molecules that are down-modulated with later passage include CD24, CD54, CD59, CD243/P-glycoprotein, and CD273/PD-L2. Early senescence, as defined by the loss of replicative capacity occurring with the loss of differentiative capacity, increase in CDKN2A p16, and increased time to confluence, was accompanied by loss of the motility-associated metalloproteinase CD10 and the proliferation-associated transferrin receptor CD71. Among the strongest statistical associations were loss of MAC-inhibitory protein/CD59, loss of ICAM-1/CD54, and increase in CDKN2A as a function of increasing passage, as well as increased CD10 expression with adipogenic and osteogenic capacities. The data provide a clear set of markers that can be used to assess MSC quality. We suggest that clinically relevant numbers of highly functional low passage MSC can be manufactured starting with large quantities of BM, which are readily available from cadaveric organ donors.

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Section: Discussionmentioning

confidence: 99%

Proteomic Profiling of Native Unpassaged and Culture‐Expanded Mesenchymal Stromal Cells (MSC)

et al. 2018

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“…The treatment with 2 × 10 6 PLX-RAD cells injected IM on day 1 and 5 after 7.7 Gy irradiation mitigated very significantly the lethal radiation-induced ARS symptoms of weight loss and haematopoiesis failure. 26 The survival of the control irradiated vehicle treated mice by day 23 was only~20% so that higher number of mice had to be used (55) to allow enough survivors to monitor at the end of the follow-up of survival. In the group of PLX-RAD treated mice with a survival rate of almost 100% at the end of the follow-up, 31 mice were sufficient for the followed up.…”

Section: Follow-up With Time After Irradiation Of Human Plx-rad and Mmentioning

confidence: 99%

“…Placental stromal cell populations were initially investigated as an easily available alternative to BM‐MSC for stem‐cell based tissue repair. As to the trophic effect of these cells, some studies suggested that they may have advantages over stromal cells from other tissues for enhancing early development of the haematopoietic system …”

Section: Introductionmentioning

confidence: 99%

“…As to the trophic effect of these cells, some studies suggested that they may have advantages over stromal cells from other tissues for enhancing early development of the haematopoietic system. 55,56 It was previously reported that intravenously injected cells, particularly stromal cells, such as BM-MSCs, are predominantly trapped in the lung immediately following their administration. 36,57 In contrast, intramuscular (IM) injection allows the delivery of higher numbers of cells, which remain within the area of the injection site for at least 1-3 weeks with no apparent adverse effects.…”

Section: Introductionmentioning

confidence: 99%

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Rescue from lethal acute radiation syndrome (ARS) with severe weight loss by secretome of intramuscularly injected human placental stromal cells

Pinzur

Akyuez

Levdansky

et al. 2018

J cachexia sarcopenia muscle

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BackgroundMost current cell‐based regenerative therapies are based on the indirect induction of the affected tissues repair. Xenogeneic cell‐based treatment with expanded human placenta stromal cells, predominantly from fetal origin (PLX‐RAD cells), were shown to mitigate significantly acute radiation syndrome (ARS) following high dose irradiation in mice, with expedited regain of weight loss and haematopoietic function. The current mechanistic study explores the indirect effect of the secretome of PLX‐RAD cells in the rescue of the irradiated mice.MethodsThe mitigation of the ARS was investigated following two intramuscularly (IM) injected 2 × 106 PLX‐RAD cells, 1 and 5 days following 7.7 Gy irradiation. The mice survival rate and their blood or bone marrow (BM) cell counts were followed up and correlated with multiplex immunoassay of a panel of related human proteins of PLX‐RAD derived secretome, as well as endogenous secretion of related mouse proteins. PLX‐RAD secretome was also tested in vitro for its effect on the induction of the migration of BM progenitors.ResultsA 7.7 Gy whole body mice irradiation resulted in ~25% survival by 21 days. Treatment with two IM injections of 2 × 106 PLX‐RAD cells on days 1 and 5 after irradiation mitigated highly significantly the subsequent lethal ARS, with survival rate increase to nearly 100% and fast regain of the initial weight loss (P < 0,0001). This was associated with a significant faster haematopoiesis recovery from day 9 onwards (P < 0.01). Nine out of the 65 human proteins tested were highly significantly elevated in the mouse circulation, peaking on days 6–9 after irradiation, relative to negligible levels in non‐irradiated PLX‐RAD injected mice (P < 0.01). The highly elevated proteins included human G‐CSF, GRO, MCP‐1, IL‐6 and lL‐8, reaching >500 pg/mL, while MCP‐3, ENA, Eotaxin and fractalkine levels ranged between ~60–160pg/mL. The detected radiation‐induced PLX‐RAD secretome correlated well with the timing of the fast haematopoiesis regeneration. The radiation‐induced PLX‐RAD secretome seemed to reinforce the delayed high levels secretion of related mouse endogenous cytokines, including GCSF, KC, MCP‐1 and IL‐6. Additional supportive in vitro studies also confirmed the ability of cultured PLX‐RAD secretome to induce accelerated migration of BM progenitors.ConclusionsA well‐regulated and orchestrated secretion of major pro‐regenerative BM supporting secretome in high dose irradiated mice, treated with xenogeneic IM injected PLX‐RAD cells, can explain the observed mitigation of ARS. This seemed to coincide with faster haematopoiesis regeneration, regain of severe weight loss and the increased survival rate. The ARS‐related stress signals activating the IM injected PLX‐RAD cells for the remote secretion of the relevant human proteins deserve further investigation.

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“…Because they have a finite life span, new MSC isolates must be continually derived and will require evaluation to determine safety and potency. All MSCs are not equivalent; they are sensitive to donor factors and to isolation and handling conditions . Every individual MSC likely has unique properties affecting potency and efficacy.…”

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confidence: 99%

Human primary fibroblasts perform similarly to MSCs in assays used to evaluate MSC safety and potency

et al. 2019

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BACKGROUND Cellular therapeutic agents may benefit trauma patients by modulating the immune response to injury, and by reducing inflammation and vascular leakage. Administration of allogeneic mesenchymal stromal cells (MSCs) shows some benefit in preclinical and clinical trials, but less testing has been performed with other cell types. Human primary fibroblasts (FBs) were compared to MSCs in assays designed to evaluate MSCs to determine if these assays actually evaluate properties unique to MSCs or whether related cell types perform similarly. STUDY DESIGN AND METHODS MSC‐related surface marker expression, tissue factor, and human leukocyte antigen–D related were evaluated by flow cytometry, and in vitro adipogenic and osteogenic differentiation potential were determined. Procoagulant activity was determined by thromboelastography. Two potency assays correlated with immunomodulation potential were utilized: the mixed lymphocyte reaction and indoleamine 2,3‐dioxygenase enzyme activity assays. RESULTS Human primary FBs performed similarly to MSCs in assays designed to evaluate MSC characteristics and potency. Although similar for MSC‐positive cell surface marker expression, FBs did not show robust adipose differentiation and expressed some level of markers not expected on MSCs. CONCLUSIONS Human primary FBs are very similar to human MSCs, at least in assays currently used to evaluate MSC potency. Preclinical and clinical testing are required to determine if FBs show similar activity to MSCs in vivo. If FBs show inferior activity in vivo, development of new MSC‐specific potency assays will be necessary to evaluate properties relevant to their unique clinical benefits.

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Placenta-derived mesenchymal stem cells possess better immunoregulatory properties compared to their cord-derived counterparts–a paired sample study

Cited by 76 publications

References 42 publications

Proteomic Profiling of Native Unpassaged and Culture‐Expanded Mesenchymal Stromal Cells (MSC)

Proteomic Profiling of Native Unpassaged and Culture‐Expanded Mesenchymal Stromal Cells (MSC)

Rescue from lethal acute radiation syndrome (ARS) with severe weight loss by secretome of intramuscularly injected human placental stromal cells

Human primary fibroblasts perform similarly to MSCs in assays used to evaluate MSC safety and potency

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