Risk of tumorigenicity in mesenchymal stromal cell–based therapies—Bridging scientific observations and regulatory viewpoints

Barkholt, Lisbeth; Flory, Egbert; Jekerle, Veronika; Lucas-Samuel, Sophie; Ahnert, Peter; Bisset, Louise; Büscher, Dirk; Fibbe, Willem E.; Foussat, Arnaud; Kwa, M.S.G.; Lantz, Olivier; Mačiulaitis, Romaldas; Palomäki, Tiina; Schneider, Christian K.; Sensebé, Luc; Tachdjian, Gérard; Tarte, Karin; Tosca, Lucie; Salmikangas, Paula

doi:10.1016/j.jcyt.2013.03.005

Cited by 334 publications

(280 citation statements)

References 30 publications

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“…As one example, the combination of osteogenic potential and targeted delivery of anticancer agents make MSCs a promising option to treat tumor-induced osteolysis (16,17). However, exogenous tissue-derived MSCs, including those from bone marrow, adipose tissues, and umbilical cord, have all shown a tendency to promote rather than inhibit cancers in many circumstances (18)(19)(20)(21)(22)(23). Also, endogenous MSCs are a major source of reactive stromal cells that promote growth and metastasis of cancers (4,24).…”

mentioning

confidence: 99%

MSCs derived from iPSCs with a modified protocol are tumor-tropic but have much less potential to promote tumors than bone marrow MSCs

Zhao¹,

Gregory²,

Lee³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

141

139

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Mesenchymal stem or stromal cells (MSCs) have many potential therapeutic applications including therapies for cancers and tissue damages caused by cancers or radical cancer treatments. However, tissue-derived MSCs such as bone marrow MSCs (BM-MSCs) may promote cancer progression and have considerable donor variations and limited expandability. These issues hinder the potential applications of MSCs, especially those in cancer patients. To circumvent these issues, we derived MSCs from transgene-free human induced pluripotent stem cells (iPSCs) efficiently with a modified protocol that eliminated the need of flow cytometric sorting. Our iPSC-derived MSCs were readily expandable, but still underwent senescence after prolonged culture and did not form teratomas. These iPSC-derived MSCs homed to cancers with efficiencies similar to BM-MSCs but were much less prone than BM-MSCs to promote the epithelial-mesenchymal transition, invasion, stemness, and growth of cancer cells. The observations were probably explained by the much lower expression of receptors for interleukin-1 and TGFβ, downstream protumor factors, and hyaluronan and its cofactor TSG6, which all contribute to the protumor effects of BM-MSCs. The data suggest that iPSC-derived MSCs prepared with the modified protocol are a safer and better alternative to BM-MSCs for therapeutic applications in cancer patients. The protocol is scalable and can be used to prepare the large number of cells required for "off-the-shelf" therapies and bioengineering applications.

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mentioning

confidence: 99%

MSCs derived from iPSCs with a modified protocol are tumor-tropic but have much less potential to promote tumors than bone marrow MSCs

Zhao¹,

Gregory²,

Lee³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

141

139

View full text Add to dashboard Cite

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“…[3]/46,XY [20] 46,XY,der(7)dup(7)(q32q36)t(7;?)(q36;?) [3]/46,XY [20] 12 46,XY,der(7)dup(7)(q32q36)t(7;?) (q36;?)…”

Section: Discussionmentioning

confidence: 99%

“…An expanding number of clinical trials has been conducted to examine the potential therapeutic applications of MSCs. However, the clinical use of MSCs is still controversial, due to concerns about their safety [1][2][3]. The most important concern is the tumorigenesis potential of the MSCs [4][5][6][7].…”

Section: Introductionmentioning

confidence: 99%

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Asymmetric Aneuploidy in Mesenchymal Stromal Cells Detected by In Situ Karyotyping and Fluorescence In Situ Hybridization: Suggestions for Reference Values for Stem Cells

Kim

Park

et al. 2015

Stem Cells and Development

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Cytogenetic testing is important to ensure patient safety before therapeutic application of mesenchymal stromal cells (MSCs). However, the standardized methods and criteria for the screening of chromosomal abnormalities of MSCs have not yet been determined. We investigated the frequency of cytogenetic aberrations in MSCs using G-banding and fluorescence in situ hybridization (FISH) and suggest reference values for aneuploidy in MSCs. Cytogenetic analysis was performed on 103 consecutive cultures from 68 MSCs (25 adipose-origin, 20 bone marrow-origin, 18 cord blood-origin, and 5 neural stem cells; 8 from adipose tissue of patients with breast cancer and 60 from healthy donors). We compared the MSC aneuploidy patterns with those of hematological malignancies and benign hematological diseases. Interphase FISH showed variable aneuploid clone proportions (1%-20%) in 68 MSCs. The aneuploidy patterns were asymmetric, and aneuploidy of chromosomes 16, 17, 18, and X occurred most frequently. Clones with polysomy were significantly more abundant than those with monosomy. The cutoff value of maximum polysomy rates (upper 95th percentile value) was 13.0%. By G-banding, 5 of the 61 MSCs presented clonal chromosomal aberrations. Aneuploidy was asymmetric in the malignant hematological diseases, while it was symmetric in the benign hematological diseases. We suggest an aneuploidy cutoff value of 13%, and FISH for aneuploidy of chromosomes 16, 17, 18, and X would be informative to evaluate the genetic stability of MSCs. Although it is unclear whether the aneuploid clones might represent the senescent cell population or transformed cells, more attention should be focused on the safety of MSCs, and G-banding combined with FISH should be performed.

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“…A pathogenic variation can prompt sickness or cause various disarrange. Nonetheless, comprehension of pathogenic instruments makes an chance to anticipate serious results by creating novel analytic devices and by planning very successful medications for the infection (5,6). To accomplish this point it is important to perform extensive scale useful genome examination that includes diverse fields of study: genomics, epigenomics, transcriptomics, proteomics, and interactomics.…”

Section: Introductionmentioning

confidence: 99%

A Survey of Methods for Genome Functional Analysis in Comparative Genomics

Udayaraju¹,

Varma²,

Sujitha³

2018

IJET

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In biomedical technologies, Gene functional analysis is an emerging concept in understands the DNA sequence and gene product analysis and gene interaction in different real time medical applications. Finding data sequences of gene functionalities. There are many techniques have been used to progress functionality of functionality of genome analysis. In this paper, we present algorithmic, calculation oriented and mathematical comparison under analysis of genome. We develop techniques for dynamic and automatic calculation of Genome relations; these relations are enabled in automatic identification of orthodox for Genome from redundant Genes in yeast Genome. We present a method to identify automatic protein to protein interaction Based on related patterns related to specific presentations, we observe understand frame of functional proteins were developed to find Gene identification with accurate and reliable formations like sensitivity & specificity. We also present methods for systematic "denovo" identification of motifs. The techniques do not depend on previous information of gene operate and in that way stand out from the present literary works on computational design finding. Based on the genome-wide preservation styles of known elements, we designed three preservation requirements that we used to discover novel motifs. Our comparative results give comparative genomic to process our outstanding of any pieces. Our proposed techniques are flexible to verify comprehensive data genes and provide reliable research on complicated genomes on human specifications.

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Risk of tumorigenicity in mesenchymal stromal cell–based therapies—Bridging scientific observations and regulatory viewpoints

Cited by 334 publications

References 30 publications

MSCs derived from iPSCs with a modified protocol are tumor-tropic but have much less potential to promote tumors than bone marrow MSCs

MSCs derived from iPSCs with a modified protocol are tumor-tropic but have much less potential to promote tumors than bone marrow MSCs

Asymmetric Aneuploidy in Mesenchymal Stromal Cells Detected by In Situ Karyotyping and Fluorescence In Situ Hybridization: Suggestions for Reference Values for Stem Cells

A Survey of Methods for Genome Functional Analysis in Comparative Genomics

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