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Novel Reprogramming Approach for Cardiosphere-based Myocardial Regeneration

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Review of “Generation of Induced Cardiospheres via Reprogramming of Skin Fibroblasts for Myocardial Regeneration” from Stem Cells by Stuart P. Atkinson

Current stem cell therapies for the damaged heart mainly rely on the secretion of paracrine factors to support endogenous cells and not cellular transdifferentiation into replacement cardiomyocytes. Encouragingly, a population of cardiac progenitor cells derived from endogenous cardiospheres (eCS) can differentiate into cardiomyocytes in vivo [1, 2] and may represent an enhanced stem cell strategy for myocardial regeneration.

Unfortunately, the source for patient-specific/autologous eCS cells comes from invasive heart biopsies which provide scant numbers of cells. As an alternative, researchers from the lab of Hung-Fat Tse (University of Hong Kong, China) aimed to modify a fibroblast-to-cardiomyocyte reprogramming approach [3] and capture eCS cells as they pass through a cardiac progenitor stage [4]. Can this new strategy provide the cell numbers we need to make cardiosphere-based myocardial regeneration a clinical reality? 

The novel reprogramming approach employed the retroviral transduction of Oct4, Sox2, and Klf4 in mouse embryonic and adult fibroblasts followed by treatment with the GSK3β Inhibitor BIO and the pleiotropic cytokine Oncostatin M (OSM). After plating cells onto poly-D-lysine coated plates, only cells treated with these two compounds formed induced cardiospheres (iCS) which resembled eCS isolated from the mouse heart. Furthermore, cardiomyocytes differentiated from both induced and endogenous CSs displayed similar functional characteristics, although both types of cardiomyocytes were less mature than native cardiomyocytes.

However, the transplantation of iCS and eCS cells into the heart of a mouse model of myocardial infarction mediated a similar positive effect on functionality and correlated to the differentiation of both cell types into cardiomyocytes (See Figure – iCS- and eCS-derived cells express GFP).

Great for the mouse, but what about humans?! The authors addressed this point by adapting the protocol to use human fibroblasts as their starting material and successfully produced human iCS which could differentiate into cardiomyocytes in vitro. 

Great news! This new novel reprogramming approach may now allow us to generate large amounts of patient-specific CSs and thereby realize the full potential of cardiosphere-based myocardial regeneration [5, 6]. However, Xu et al do note a few small improvements required to enhance the likelihood of clinical application. Such performance-enhancing alterations will include reprogramming using non-integrating vectors or small molecules, the identification of the specific cell within the CS populations which provides therapeutic benefit, and the long-term consequences of CS cell transplantation. 

Keep tuned to the Stem Cells Portal to find out how this novel reprogramming approach evolves!

Discussion Points

  1. Can we use this strategy to “capture” other progenitor/stem cell populations?
  2. Do CS cells derived using this strategy retain long term functionality?
  3. What other improvements can be made to improve the efficacy and the clinical potential of iCS-derived cells?

References

  1. Messina E, De Angelis L, Frati G, et al. Isolation and expansion of adult cardiac stem cells from human and murine heart. Circ Res 2004;95:911-921.
  2. Smith RR, Barile L, Cho HC, et al. Regenerative potential of cardiosphere-derived cells expanded from percutaneous endomyocardial biopsy specimens. Circulation 2007;115:896-908.
  3. Efe JA, Hilcove S, Kim J, et al. Conversion of mouse fibroblasts into cardiomyocytes using a direct reprogramming strategy. Nat Cell Biol 2011;13:215-222.
  4. Xu J-Y, Lee Y-K, Ran X, et al. Generation of Induced Cardiospheres via Reprogramming of Skin Fibroblasts for Myocardial Regeneration. STEM CELLS 2016;34:2693-2706.
  5. Ishigami S, Ohtsuki S, Tarui S, et al. Intracoronary autologous cardiac progenitor cell transfer in patients with hypoplastic left heart syndrome: the TICAP prospective phase 1 controlled trial. Circ Res 2015;116:653-664.
  6. Simpson DL, Mishra R, Sharma S, et al. A strong regenerative ability of cardiac stem cells derived from neonatal hearts. Circulation 2012;126:S46-53.