Gladstone Institute Scientists Devise New Way to Make Heart Cells from Skin Cells Opening the Door to the Possibility of Personalized Medicine for Heart Attack Patients


Gladstone Institute research scientists have devised a new way to make heart replacement cells. This novel protocol generates cells that lie in between embryonic stem cells and adult heart cells. These induced expandable cardiovascular progenitor cells (ieCPCs) might very well hold the key to treating heart disease. Even though ieCPCs can develop into heart cells, they still have the ability to grow and expand in culture to produce the large numbers of cells required for clinical purposes. When these ieCPCs are injected directly into the hearts of laboratory mice that have recently suffered a heart attack, they formed heart muscle cells and other heart-specific cell types and significantly improved heart function.

Yu Zhang, MD, PhD, lead author on the study and a postdoctoral scholar at the Gladstone Institutes said, “Scientists have tried for decades to treat heart failure by transplanting adult heart cells, but these cells cannot reproduce themselves, and so they do not survive in the damaged heart.” Zhang continued, “Our generated ieCPCs can prolifically replicate and reliably mature into the three types of cells in the heart, which makes them a very promising potential treatment for heart failure.”

CPCs or cardiovascular progenitor cells are the result of embryonic development and help form the embryonic heart. In the embryo, CPCs can differentiate into a wide variety of different heart-specific cells. This Gladstone Institute study, which was published in the journal Cell Stem Cell, Zhang and his colleagues reprogrammed mouse embryonic fibroblasts into CPCs in the laboratory. Once the mouse embryonic fibroblasts had been reprogrammed into CPCs, Zhang and others used a special medium to keep the cells from differentiating into fully-mature, functional heart cells that no longer were able to divide.

CPCs constitute so-called “organ-specific stem cells.” Organ-specific stem cells are special because they can differentiate into adult cells and, under the right conditions, grow, expand and proliferate in culture indefinitely. Zhang and his colleagues were able to expand their ieCPC cultures for over a dozen generations. This generated more than enough cells to treat several patients.

The importance of the ability of these cells to expand in the laboratory cannot be undersold. When a patient suffers a heart attack, over one billion heart cells can die off. Robust cell renewal means ieCPCs can play the role of a sustainable source of cells that can replace the cells that died as a result of the heat attack. Furthermore, ieCPCs can also develop into each of the three different types of heart cells: cardiomyocytes (heart muscle cells), endothelial cells (blood vessel cells), and smooth muscle cells (that surround the blood vessels and regulate their diameter).. When ieCPCs were injected into a mouse hearts, they spontaneously differentiated into each of these heart-specific cell types without requiring any further coaxing or signals.

Previous attempts to treat heart failure by transplanting adult heart cells have produced, for the most part, modest results. Implanted cells tend to survive poorly and do not self-renew, which seriously compromises their ability to repopulate and heal a damaged heart. An additional caveat is that regenerating the heart after a heart attack requires that the heart be supplied with more than just heart muscle cells (cardiomyocytes). Instead the heart needs all three cell types;

Clinical trials that have tested the ability of non-cardiac stem cells to heal the heart after a heart attack have also shown modest, though limited success. In this case, the implanted cells only differentiate into heart-specific cells types rather poorly. Such transdifferentiation events require complex signals that are absent in an adult heart. ieCPCs circumvent these issues since they are already heart-specific progenitor cells that are committed to forming heart-specific cell types.

In this study, 90% of the injected ieCPCs were retained in a mouse heart after a heart attack and successfully differentiated into functioning heart cells. The ieCPCs formed cardiomyocytes that integrated into the myocardium and formed functional connections with existing, surviving cardiomyocytes. The ability to connect with existing heart muscle cells is also crucial to minimize the risk of arrhythmias after a heart attack. The implanted ieCPCs also created new blood vessels that pumped blood and oxygen to newly-forming heart tissues. The ieCPCs significantly improved heart function. The mouse hearts pumped more efficiently, and the benefits lasted for at least three months. Because these cells are generated from skin cells, this procedure also opens the door for personalized medicine in which a heart patient’s own cells are used to treat their heart disease.

iceC-Figure6

ieCPCs Give Rise to CMs, ECs, and SMCs In Vivo and Improve Cardiac Function after MI

(A–E) Immunofluorescence analyses of RFP and CM (A), EC (B and C), and SMC (D and E) markers in tissue sections collected 2 weeks after transplanting RFP-labeled ieCPCs at passage 10 into infarcted hearts of immunodeficient mice. Scale bars represent 100 μm.

(F and G) Ejection fraction and fractional shortening of the left ventricle (LV) quantified by echocardiography. Results from two independent experiments were shown. D, days; W, weeks.

(H–J) Cardiac fibrosis was evaluated at eight levels (L1–L8) by Masson’s trichrome staining 12 weeks after coronary ligation. The ligation site is marked as X. Sections of representative hearts are shown in (I) with quantification in (J). Scar tissue (%) = (the sum of fibrotic area or length at L1–L8/the sum of LV area or circumference at L1–L8) × 100. Scale bars represent 500 μm.

(K) Quantification of LV circumference of mouse hearts 12 weeks after transplantation of 2nd MEFs or ieCPCs. Data were summarized from 48 sections for each group. Data are mean ± SE. p < 0.05.

“Cardiac progenitor cells could be ideal for heart regeneration,” said senior author Sheng Ding, PhD, a senior investigator at Gladstone. “They are the closest precursor to functional heart cells, and, in a single step, they can rapidly and efficiently become heart cells, both in a dish and in a live heart. With our new technology, we can quickly create billions of these cells in a dish and then transplant them into damaged hearts to treat heart failure.”

 

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mburatov

Professor of Biochemistry at Spring Arbor University (SAU) in Spring Arbor, MI. Have been at SAU since 1999. Author of The Stem Cell Epistles. Before that I was a postdoctoral research fellow at the University of Pennsylvania in Philadelphia, PA (1997-1999), and Sussex University, Falmer, UK (1994-1997). I studied Cell and Developmental Biology at UC Irvine (PhD 1994), and Microbiology at UC Davis (MA 1986, BS 1984).

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