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Potential Strategies to Address the Major Clinical Barriers Facing Stem Cell Regenerative Therapy for Cardiovascular Disease: A Review.

ABSTRACT: Although progress continues to be made in the field of stem cell regenerative medicine for the treatment of cardiovascular disease, significant barriers to clinical implementation still exist.To summarize the current barriers to the clinical implementation of stem cell therapy in patients with cardiovascular disease and to discuss potential strategies to overcome them.Information for this review was obtained through a search of PubMed and the Cochrane database for English-language studies published between January 1, 2000, and July 25, 2016. Ten randomized clinical trials and 8 systematic reviews were included.One of the major clinical barriers facing the routine implementation of stem cell therapy in patients with cardiovascular disease is the limited and inconsistent benefit observed thus far. Reasons for this finding are unclear but may be owing to poor cell retention and survival, as suggested by numerous preclinical studies and a small number of human studies incorporating imaging to determine cell fate. Additional studies in humans using imaging to determine cell fate are needed to understand how these factors contribute to the limited efficacy of stem cell therapy. Treatment strategies to address poor cell retention and survival are under investigation and include the following: coadministration of immunosuppressive and prosurvival agents, delivery of cardioprotective factors packaged in exosomes rather than the cells themselves, and use of tissue-engineering strategies to provide structural support for cells. If larger grafts are achieved using these strategies, it will be imperative to carefully monitor for the potential risks of tumorigenicity, immunogenicity, and arrhythmogenicity.Despite important achievements to date, stem cell therapy is not yet ready for routine clinical implementation. Significant research is still needed to address the clinical barriers outlined herein before the next wave of large clinical trials is under way.

SUBMITTER: Nguyen PK

PROVIDER: S-EPMC5378463 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Potential Strategies to Address the Major Clinical Barriers Facing Stem Cell Regenerative Therapy for Cardiovascular Disease: A Review.

Nguyen Patricia K PK Neofytou Evgenios E Rhee June-Wha JW Wu Joseph C JC

JAMA cardiology 20161101 8

<h4>Importance</h4>Although progress continues to be made in the field of stem cell regenerative medicine for the treatment of cardiovascular disease, significant barriers to clinical implementation still exist.<h4>Objectives</h4>To summarize the current barriers to the clinical implementation of stem cell therapy in patients with cardiovascular disease and to discuss potential strategies to overcome them.<h4>Evidence review</h4>Information for this review was obtained through a search of PubMed ...[more]

PMID: 27579998

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Project description:BackgroundA fundamental challenge of implementation is identifying contextual determinants (i.e., barriers and facilitators) and determining which implementation strategies will address them. Numerous conceptual frameworks (e.g., the Consolidated Framework for Implementation Research; CFIR) have been developed to guide the identification of contextual determinants, and compilations of implementation strategies (e.g., the Expert Recommendations for Implementing Change compilation; ERIC) have been developed which can support selection and reporting of implementation strategies. The aim of this study was to identify which ERIC implementation strategies would best address specific CFIR-based contextual barriers.MethodsImplementation researchers and practitioners were recruited to participate in an online series of tasks involving matching specific ERIC implementation strategies to specific implementation barriers. Participants were presented with brief descriptions of barriers based on CFIR construct definitions. They were asked to rank up to seven implementation strategies that would best address each barrier. Barriers were presented in a random order, and participants had the option to respond to the barrier or skip to another barrier. Participants were also asked about considerations that most influenced their choices.ResultsFour hundred thirty-five invitations were emailed and 169 (39%) individuals participated. Respondents had considerable heterogeneity in opinions regarding which ERIC strategies best addressed each CFIR barrier. Across the 39 CFIR barriers, an average of 47 different ERIC strategies (SD = 4.8, range 35 to 55) was endorsed at least once for each, as being one of seven strategies that would best address the barrier. A tool was developed that allows users to specify high-priority CFIR-based barriers and receive a prioritized list of strategies based on endorsements provided by participants.ConclusionsThe wide heterogeneity of endorsements obtained in this study's task suggests that there are relatively few consistent relationships between CFIR-based barriers and ERIC implementation strategies. Despite this heterogeneity, a tool aggregating endorsements across multiple barriers can support taking a structured approach to consider a broad range of strategies given those barriers. This study's results point to the need for a more detailed evaluation of the underlying determinants of barriers and how these determinants are addressed by strategies as part of the implementation planning process.

Project description:BackgroundThe school-located influenza vaccinations (SLIV) can increase influenza vaccination and reduce influenza infections among school-aged children. However, the vaccination rate has remained low and varied widely among schools in Beijing, China. This study aimed to ascertain barriers and facilitators of implementing SLIV and to identify implementation strategies for SLIV quality improvement programs in this context.MethodsSemi-structured interviews were conducted with diverse stakeholders (i.e., representatives of both the Department of Health and the Department of Education, school physicians, class headteachers, and parents) involved in SLIV implementation. Participants were identified by purposive and snowball sampling. The Consolidated Framework for Implementation Research was adopted to facilitate data collection and analysis. Themes and subthemes regarding barriers and facilitators were generated using deductive and inductive approaches. Based on the Consolidated Framework for Implementation Research-Expert Recommendations for Implementing Change (CFIR-ERIC) matching tool, practical implementation strategies were proposed to address the identified barriers of SLIV delivery.ResultsTwenty-four participants were interviewed. Facilitators included easy access to SLIV, clear responsibilities and close collaboration among government sectors, top-down authority, integrating SLIV into the routine of schools, and priority given to SLIV. The main barriers were parents' misconception, inefficient coordination for vaccine supply and vaccination dates, the lack of planning, and inadequate access to knowledge and information about the SLIV. CFIR-ERIC Matching tool suggested implementation strategies at the system (i.e., developing an implementation blueprint, and promoting network weaving), school (i.e., training and educating school implementers), and consumer (i.e., engaging students and parents) levels to improve SLIV implementation.ConclusionsThere were substantial barriers to the delivery of the SLIV program. Theory-driven implementation strategies developed in this pre-implementation study should be considered to address those identified determinants for successful SLIV implementation.

Project description:STUDY QUESTION:Is endosialin a specific marker of human stem Leydig cells (SLCs) with the ability to differentiate into testosterone-producing Leydig cells (LCs) in vitro and in vivo? SUMMARY ANSWER:Endosialin is a specific marker of human SLCs which differentiate into testosterone-producing LCs in vitro and in vivo. WHAT IS KNOWN ALREADY:Human SLCs have been identified and isolated using the marker platelet-derived growth factor receptor ? (PDGFR?) or nerve growth factor receptor (NGFR). However, the specificity was not high; thus, LCs and germ cells could be mistakenly sorted as SLCs if PDGFR? or NGFR was used as a marker for human SLCs isolation. STUDY DESIGN, SIZE, DURATION:Firstly, we re-evaluated the specificity of PDGFR? and NGFR for SLCs in adult human testes. Then we analysed the previously published single-cell sequencing data and found that endosialin may identify human SLCs. Subsequently, we sorted endosialin+ cells from four human donors and characterized their self-renewal and multipotent properties. To assess whether endosialin+ cells have the potential to differentiate into functional LCs in vitro, these cells were stimulated by differentiation-inducing medium. We next assessed the in vivo regenerative potential of human endosialin+ cells after xenotransplantation into the testes of immunodeficient mice. PARTICIPANTS/MATERIALS, SETTING, METHODS:Single-cell sequencing analysis, immunofluorescence and flow cytometry were used to characterize human testis tissues. In vitro colony formation, multipotent differentiation (adipogenic, osteogenic and chondrogenic) and Leydig cell-lineage induction were used to assess stem cell activity. Xenotransplantation into 3-week-old immunodeficient mice was used to determine in vivo regenerative potential. Endpoint measures included testosterone measurements, cell proliferation, immunofluorescence, flow cytometry and quantitative RT-PCR. MAIN RESULTS AND THE ROLE OF CHANCE:The results indicate that endosialin is a specific marker of SLCs compared with PDGFR? and NGFR. Additionally, endosialin+ cells isolated from human testes show extensive proliferation and differentiation potential in vitro: their self-renewal ability was inferred by the formation of spherical clones derived from a single cell. Moreover, these cells could differentiate into functional LCs that secreted testosterone in response to LH in a concentration-dependent manner in vitro. These self-renewal and differentiation properties reinforce the proposal that human testicular endosialin+ cells are SLCs. Furthermore, transplanted human endosialin+ cells appear to colonize the murine host testes, localize to peritubular and perivascular regions, proliferate measurably and differentiate partially into testosterone-producing LCs in vivo. LARGE SCALE DATA:NA. LIMITATIONS, REASONS FOR CAUTION:Owing to the difficulty in collecting human testis tissue, the sample size was limited. The functions of endosialin on SLCs need to be elucidated in future studies. WIDER IMPLICATIONS OF THE FINDINGS:A discriminatory marker, endosialin, for human SLCs purification is a prerequisite to advance research in SLCs and logically promote further clinical translation of SLCs-based therapies for male hypogonadism. STUDY FUNDING/COMPETING INTEREST(S):A.P.X. was supported by the National Key Research and Development Program of China (2017YFA0103802 and 2018YFA0107200). C.D. was supported by the National Natural Science Foundation of China (81971314) and the Natural Science Foundation of Guangdong Province, China (2018B030311039). The authors declare no conflict of interest.

Dataset Information

Potential Strategies to Address the Major Clinical Barriers Facing Stem Cell Regenerative Therapy for Cardiovascular Disease: A Review.

Publications

Potential Strategies to Address the Major Clinical Barriers Facing Stem Cell Regenerative Therapy for Cardiovascular Disease: A Review.

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