Therapeutic Potential of Wharton’s Jelly Mesenchymal Stem Cells for Diabetes: Achievements and Challenges

Kamal, Mohamed M.; Kassem, Dina H.

doi:10.3389/fcell.2020.00016

Cited by 52 publications

(35 citation statements)

References 129 publications

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“…This might be complicated by the lack of standardized cryo-preservation protocols for WJ-MSCs, unlike UCB whose banking procedures are well-established [ 50 ]. In fact, well-standardized cryo-preservation/banking protocols for GMP-compliant clinical grade WJ-MSCs are indeed warranted and considered to be among the major challenges for successful translation of WJ-MSCs from bench to bed-side [ 51 ].…”

Section: Discussionmentioning

confidence: 99%

Therapeutic efficacy of umbilical cord-derived stem cells for diabetes mellitus: a meta-analysis study

Kassem

Kamal

2020

Stem Cell Res Ther

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Background Stem cell therapy provides great hope for patients with diabetes mellitus (DM). DM is a seriously alarming metabolic disease characterized by hyperglycemia and β cell dysfunction. Efficient novel therapeutic modalities to treat DM are indeed warranted. Stem cells (SC) derived from the umbilical cord specifically provide several advantages and unique characteristics being a readily available non-invasive source, with an additional credit for their banking potential. This meta-analysis study aims to provide a focused assessment for therapeutic efficacy of umbilical cord (UC)-derived SC-transplantation, namely Wharton’s jelly mesenchymal stem cells (WJ-MSCs) and umbilical cord blood (UCB) for DM. Methods The clinical efficacy was evaluated based on glycemic control status (reflected on HbA1c%) and β cell function (reflected on C-peptide levels), as well as the daily insulin requirement in diabetic patients after receiving UC-derived SC-transplantation compared to baseline values. Moreover, we assessed these outcome measures in patients who received such intervention compared to those who did not receive it in randomized/non-randomized controlled clinical trials. We employed a random-effects model and standardized mean difference for this meta-analysis. Results Eleven eligible clinical studies were included; WJ-MSCs (6 studies; 172 patients including 71 controls) and UCB (5 studies; 74 patients including 15 controls). WJ-MSCs significantly improved HbA1c% (pooled-estimate − 1.085; 95%CI (− 1.513, − 0.657); p < 0.001) and C-peptide levels (pooled-estimate 1.008; 95%CI (0.475, 1.541); p < 0.001), as well as the daily insulin-requirement (pooled-estimate − 2.027; 95%CI (− 3.32, − 0.733); p = 0.002). On the contrary, UCB was found to be uniformly ineffective; HbA1c% (pooled-estimate − 0.091, 95%CI (− 0.454, 0.271); p = 0.622), significantly deteriorated C-peptide levels (pooled-estimate − 0.789; 95%CI (− 1.252, − 0.325); p < 0.001) and daily insulin-requirement (pooled-estimate 0.916; 95%CI (0.247, 1.585); p = 0.007). All these observations remained consistent when we carried out sub-group meta-analysis for T1DM and T2DM and also when we compared patients who received WJ-MSCs or UCB to controls. Conclusions The results of our meta-analysis provide a clear evidence for the superior efficacy of WJ-MSCs over UCB in DM. This sheds lights on the importance to consider banking of WJ-MSCs together with the well-established routine UCB-banking, especially for those with family history of DM. Additionally, further clinical studies are required to investigate therapeutic efficacy of selected/enriched UCB-derived cell populations with immunomodulatory/regenerative potential in DM.

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Section: Discussionmentioning

confidence: 99%

Therapeutic efficacy of umbilical cord-derived stem cells for diabetes mellitus: a meta-analysis study

Kassem

Kamal

2020

Stem Cell Res Ther

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“…Mesenchymal stem cells (MSCs) are multipotent cells with a fibroblast-like morphology that are considered a lifelong cellular reservoir to ensure the continuous generation, replacement, and restitution of multiple tissue lineages ( 224 – 226 ). MSCs regenerative properties are mediated by their ability to infiltrate and engraft injured areas, where they reduce inflammation, promote angiogenesis, prevent apoptosis, improve scar formation, and mediate tissue remodeling via the paracrine secretion of chemokines and growth factors ( 227 , 228 ).…”

Section: Diabetics' Stem Cells Are Not Exempted From Senescencementioning

confidence: 99%

Cellular Senescence as the Pathogenic Hub of Diabetes-Related Wound Chronicity

et al. 2020

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Diabetes is constantly increasing at a rate that outpaces genetic variation and approaches to pandemic magnitude. Skin cells physiology and the cutaneous healing response are progressively undermined in diabetes which predisposes to lower limb ulceration, recidivism, and subsequent lower extremities amputation as a frightened complication. The molecular operators whereby diabetes reduces tissues resilience and hampers the repair mechanisms remain elusive. We have accrued the notion that diabetic environment embraces preconditioning factors that definitively propel premature cellular senescence, and that ulcer cells senescence impair the healing response. Hyperglycemia/oxidative stress/mitochondrial and DNA damage may act as major drivers sculpturing the senescent phenotype. We review here historical and recent evidences that substantiate the hypothesis that diabetic foot ulcers healing trajectory, is definitively impinged by a self-expanding and self-perpetuative senescent cells society that drives wound chronicity. This society may be fostered by a diabetic archetypal secretome that induces replicative senescence in dermal fibroblasts, endothelial cells, and keratinocytes. Mesenchymal stem cells are also susceptible to major diabetic senescence drivers, which accounts for the inability of these cells to appropriately assist in diabetics wound healing. Thus, the use of autologous stem cells has not translated in significant clinical outcomes. Novel and multifaceted therapeutic approaches are required to pharmacologically mitigate the diabetic cellular senescence operators and reduce the secondary multi-organs complications. The senescent cells society and its adjunctive secretome could be an ideal local target to manipulate diabetic ulcers and prevent wound chronification and acute recidivism. This futuristic goal demands harnessing the diabetic wound chronicity epigenomic signature.

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“…Such allogeneic use is possible because MSCs are considered to be immune evasive (Ankrum et al, 2014). Autologous cells may be an attractive option, available even from perinatal tissue when cryostored-here, however, the system of cryobanks needs to be expanded (Bieback and Brinkmann, 2010;Brown et al, 2019;Kamal and Kassem, 2020). However, the prerequisite for use of autologous cells is that they are not affected by the disease to be treated or by comorbidities.…”

Section: Choice Of Donor and Recipientmentioning

confidence: 99%

Limited Potential or Unfavorable Manipulations? Strategies Toward Efficient Mesenchymal Stem/Stromal Cell Applications

Lavrentieva

Hoffmann

Lee-Thedieck

2020

Front. Cell Dev. Biol.

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Despite almost 50 years of research and over 20 years of preclinical and clinical studies, the question of curative potential of mesenchymal stem/stromal cells (MSCs) is still widely discussed in the scientific community. Non-reproducible treatment outcomes or even absence of treatment effects in comparison to control groups challenges the potential of these cells for routine application both in tissue engineering and in regenerative medicine. One of the reasons of such outcomes is non-standardized and often disadvantageous ex vivo manipulation of MSCs prior therapy. In most cases, clinically relevant cell numbers for MSC-based therapies can be only obtained by in vitro expansion of isolated cells. In this mini review, we will discuss point by point possible pitfalls in the production of human MSCs for cell therapies, without consideration of material-based applications. Starting with cell source, choice of donor and recipient, as well as isolation methods, we will then discuss existing expansion protocols (two-/three-dimensional cultivation, basal medium, medium supplements, static/dynamic conditions, and hypoxic/normoxic conditions) and influence of these strategies on the cell functionality after implantation. The role of potency assays will also be addressed. The final aim of this mini review is to illustrate the heterogeneity of current strategies for gaining MSCs for clinical applications with their strengths and weaknesses. Only a careful consideration and standardization of all pretreatment processes/methods for the different applications of MSCs will ensure robust and reproducible performance of these cell populations in the different experimental and clinical settings.

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Therapeutic Potential of Wharton’s Jelly Mesenchymal Stem Cells for Diabetes: Achievements and Challenges

Cited by 52 publications

References 129 publications

Therapeutic efficacy of umbilical cord-derived stem cells for diabetes mellitus: a meta-analysis study

Therapeutic efficacy of umbilical cord-derived stem cells for diabetes mellitus: a meta-analysis study

Cellular Senescence as the Pathogenic Hub of Diabetes-Related Wound Chronicity

Limited Potential or Unfavorable Manipulations? Strategies Toward Efficient Mesenchymal Stem/Stromal Cell Applications

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