Defining the risks of mesenchymal stromal cell therapy

Prockop, Darwin J.; Brenner, Malcolm K.; Fibbe, Willem E.; Horwitz, Edwin M.; Blanc, Katarina Le; Phinney, Donald G.; Simmons, Paul J.; Sensebé, Luc; Keating, Armand

doi:10.3109/14653249.2010.507330

Cited by 292 publications

(198 citation statements)

References 14 publications

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“…Furthermore, when these transformed ASC were implanted in immunodeficient mice, they formed sarcomas in vivo. Similar evidence from work using bone marrow MSCs has led to a policy statement by the ISCT regarding tumorigenesis [37]. While there is evidence suggesting that not all reported transformations in culture were actual events, it is incumbent on the stem cell community to take the most conservative approach with respect to patient safety.…”

Section: Tumorigenesismentioning

confidence: 88%

Concise Review: Adipose-Derived Stromal Vascular Fraction Cells and Stem Cells: Let's Not Get Lost in Translation

et al. 2011

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Subcutaneous fat has emerged as an alternative tissue source for stromal/stem cells in regenerative medicine. Over the past decade, international research efforts have established a wealth of basic science and preclinical evidence regarding the differentiation potential and regenerative properties of both freshly processed, heterogeneous stromal vascular fraction cells and culture expanded, relatively homogeneous adipose-derived stromal/stem cells. The stage has been set for clinicians to translate adipose-derived cells from the bench to the bedside; however, this process will involve “development” steps that fall outside of traditional “hypothesis-driven, mechanism-based” paradigm. This concise review examines the next stages of the development process for therapeutic applications of adipose-derived cells and highlights the current state of the art regarding clinical trials. It is recommended that the experiments addressing these issues be reported comprehensively in the peer-review literature. This transparency will accelerate the standardization and reproducibility of adipose-derived cell therapies with respect to their efficacy and safety.

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Section: Tumorigenesismentioning

confidence: 88%

Concise Review: Adipose-Derived Stromal Vascular Fraction Cells and Stem Cells: Let's Not Get Lost in Translation

et al. 2011

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“…Thus, for clinically significant OI caused by structural defects in collagen, suppression of the Mut allele could in principle convert severe types III and IV to the minimally symptomatic OI type I, a situation particularly favorable to therapeutic strategies based on gene silencing. The promising preliminary data on stem cell transplantation in both murine models [18][19][20] and human OI 21,22 contributes to an appealing possibility for correcting the patient's own stem cells in vitro, and transplanting them back to the patient, after checking chromosomal rearrangements 23 or off-target effects 24 in vitro.…”

Section: Introductionmentioning

confidence: 99%

Allele-specific Col1a1 silencing reduces mutant collagen in fibroblasts from Brtl mouse, a model for classical osteogenesis imperfecta

et al. 2013

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Gene silencing approaches have the potential to become a powerful curative tool for a variety of monogenic diseases caused by gain-of-function mutations. Classical osteogenesis imperfecta (OI), a dominantly inherited bone dysplasia, is characterized in its more severe forms by synthesis of structurally abnormal type I collagen, which exerts a negative effect on extracellular matrix. Specific suppression of the mutant (Mut) allele would convert severe OI forms to the mild type caused by a quantitative defect in normal collagen. Here, we describe the in vitro and ex vivo investigation of a small interfering RNA (siRNA) approach to allele-specific gene silencing using Mut Col1a1 from the Brtl mouse, a well-characterized model for classical human OI. A human embryonic kidney cell line, which expresses the firefly luciferase gene, combined with either wild-type or Mut Brtl Col1a1 exon 23 sequences, was used for the first screening. The siRNAs selected based on their specificity and the corresponding short hairpin RNAs (shRNAs) subcloned in a lentiviral vector were evaluated ex vivo in Brtl fibroblasts for their effect on collagen transcripts and protein. A preferential reduction of the Mut allele of up to 52% was associated with about 40% decrease of the Mut protein, with no alteration of cell proliferation. Interestingly, a downregulation of HSP47, a specific collagen chaperone known to be upregulated in some OI cases, was detected. Our data support further testing of shRNAs and their delivery by lentivirus as a strategy to specifically suppress the Mut allele in mesenchymal stem cells of OI patients for autologous transplantation.

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“…Spontaneous transformation of MSCs with emergence from senescence has been reported for murine MSCs cultured ex vivo [1]. The risk with human MSCs appears considerably lower, however, and chromosomal aberrations have only been detected in cultured cells undergoing senescence [2][3][4].…”

Section: Introductionmentioning

confidence: 99%

Analysis of Tissues Following Mesenchymal Stromal Cell Therapy in Humans Indicates Limited Long-Term Engraftment and No Ectopic Tissue Formation

et al. 2012

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Mesenchymal stromal cells (MSCs) are explored as a novel treatment for a variety of medical conditions. Their fate after infusion is unclear, and long-term safety regarding malignant transformation and ectopic tissue formation has not been addressed in patients. We examined autopsy material from 18 patients who had received human leukocyte antigen (HLA)-mismatched MSCs, and 108 tissue samples from 15 patients were examined by PCR. No signs of ectopic tissue formation or malignant tumors of MSC-donor origin were found on macroscopic or histological examination. MSC donor DNA was detected in one or several tissues including lungs, lymph nodes, and intestine in eight patients at levels from 1/100 to <1/1,000. Detection of MSC donor DNA was negatively correlated with time from infusion to sample collection, as DNA was detected from nine of 13 MSC infusions given within 50 days before sampling but from only two of eight infusions given earlier. There was no correlation between MSC engraftment and treatment response. We conclude that MSCs appear to mediate their function through a “hit and run” mechanism. The lack of sustained engraftment limits the long-term risks of MSC therapy.

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Defining the risks of mesenchymal stromal cell therapy

Cited by 292 publications

References 14 publications

Concise Review: Adipose-Derived Stromal Vascular Fraction Cells and Stem Cells: Let's Not Get Lost in Translation

Concise Review: Adipose-Derived Stromal Vascular Fraction Cells and Stem Cells: Let's Not Get Lost in Translation

Allele-specific Col1a1 silencing reduces mutant collagen in fibroblasts from Brtl mouse, a model for classical osteogenesis imperfecta

Analysis of Tissues Following Mesenchymal Stromal Cell Therapy in Humans Indicates Limited Long-Term Engraftment and No Ectopic Tissue Formation

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