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Published on: November 3, 2011
Intrinsic cardiac origin of human cardiosphere-derived cells
Anthony J White1, Rachel R Smith, Satoshi Matsushita
1Cedars-Sinai Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
Insights
Cardiosphere-derived cells (CDCs) used in heart failure regenerative therapy originate from within the heart. Studies confirm these cells are endogenous, with no evidence of blood-borne seeding from external sources.
Area of Science:
- Cardiology
- Regenerative Medicine
- Cell Biology
Background:
- Cardiosphere-derived cells (CDCs) are a promising cell product for cardiac regeneration, expanded ex vivo from patient biopsies.
- CDCs are clonogenic, differentiate into multiple lineages, and show functional benefits in preclinical heart failure models.
- The cellular origin of CDCs (endogenous heart cells vs. blood-borne cells) is currently undetermined.
Purpose of the Study:
- To investigate the origin of cardiosphere-derived cells (CDCs) used in cardiac regenerative therapy.
- To determine if CDCs are derived from endogenous cardiac cells or from extra-cardiac sources seeding the heart.
Main Methods:
- Utilized DNA analysis (short-tandem nucleotide repeats and quantitative PCR) on donor, recipient, and CDC samples.
- Employed fluorescence in situ hybridization to detect X and Y chromosomes in CDCs from male donor/female recipient transplants.
- Leveraged donor-recipient mismatches in cardiac transplant recipients to trace cell origin.
Main Results:
- Short-tandem nucleotide repeat analysis consistently showed no recipient DNA in CDCs.
- Fluorescence in situ hybridization confirmed exclusively donor origin by detecting Y chromosomes in CDCs from male hearts transplanted into females.
- Quantitative PCR further supported the absence of recipient DNA contribution to CDCs.
Conclusions:
- Cardiosphere-derived cells are definitively of endogenous cardiac origin.
- There is no detectable contribution from extra-cardiac seeding to the CDC population.
- These findings support the use of CDCs as an autologous regenerative cell therapy for heart failure.
Aims:
Cardiosphere-derived cells (CDCs) are in clinical development as a regenerative cell product which can be expanded ex vivo from patient cardiac biopsies. Cardiosphere-derived cells are clonogenic, exhibit multilineage differentiation, and exert functional benefits in preclinical models of heart failure. The origin of CDCs remains unclear: are these cells endogenous to the heart, or do they arise from cells that populate the heart via blood-borne seeding?
Methods And Results:
Right ventricular endomyocardial biopsies were obtained from cardiac transplant recipients (n = 10, age 57 ± 15 years), and CDCs expanded from each biopsy. Donor-recipient mismatches were used to probe the origin of CDCs in three complementary ways. First, DNA analysis of short-tandem nucleotide repeats (STRs) was performed on genomic DNA from donor and recipient, then compared with the STR pattern of CDCs. Second, in two cases where the donor was male and the recipient female, CDCs were examined for the presence of X and Y chromosomes by fluorescence in situ hybridization. Finally, in two cases, quantitative PCR (qPCR) was performed for individual-specific polymorphisms of a major histocompatability locus to quantify the contribution of recipient cells to CDCs. In no case was recipient DNA detectable in the CDCs by STR analysis. In the two cases in which a female patient had received a male heart, all CDCs examined had an X and Y chromosome, similarly indicating exclusively donor origin. Likewise, qPCR on CDCs did not detect any recipient DNA.
Conclusion:
Cardiosphere-derived cells are of endogenous cardiac origin, with no detectable contribution from extra-cardiac seeding.
