Human Embryonic Stem Cells as the Model System for Understanding Molecular Controls in Human Central Nervous System (CNS) Development

San Diego Regenerative Medicine Institute and Xcelthera announce the publication of Dr. Parsons’ original research article supported by the National Institutes of Health, titled “Genome-Scale Mapping of MicroRNA Signatures in Human Embryonic Stem Cell Neurogenesis”, in Molecular Medicine & Therapeutics at http://dx.doi.org/10.4172/2324-8769.100010 & http://www.scitechnol.com/2324-8769/2324-8769-1-105.php .

Understanding the much more complex human embryonic development has been hindered by the restriction on human embryonic and fetal materials as well as the limited availability of human cell types and tissues for study. In particular, there is a fundamental gap in our knowledge regarding the molecular networks and pathways underlying the CNS and heart formation in human embryonic development. The enormous diversity of human somatic cell types and the highest order of complexity of human genomes, cells, tissues, and organs among all the eukaryotes pose a big challenge for characterizing, identifying, and validating functional elements in human embryonic development in a comprehensive manner. Derivation of human embryonic stem cells (hESCs) provides a powerful in vitro model system to investigate the molecular controls in human embryonic development as well as an unlimited source to generate the diversity of human cell types and subtypes across the spectrum of development stages for repair. Development and utilization of hESC models of human embryonic development will facilitate rapid progress in identification of molecular and genetic therapeutic targets for the prevention and treatment of human diseases. To tackle the shortcomings in conventional approaches, previously, we found that pluripotent hESCs maintained under the defined culture conditions can be uniformly converted into a specific lineage by small molecule induction. Our innovative small molecule direct induction approach renders a cascade of neuronal or cardiac lineage-specific progression directly from the pluripotent state of hESCs, providing much-needed in vitro model systems for investigating the human CNS development and heart formation in embryogenesis. This technology breakthrough not only opens the door for further identification of the developmental networks in human embryonic neurogenesis and cardiogenesis in a comprehensive manner, but also offers means for small-molecule-mediated direct control and modulation of the pluripotent fate of hESCs when deriving an unlimited supply of clinically-relevant lineages for regenerative medicine. Recent advances in large-scale profiling of developmental regulators in high-resolution provide powerful genome-wide high-throughput approaches that will lead to great advances in our understanding of the global phenomena of human embryogenesis. Profiling novel hESC models of human embryonic neurogenesis and cardiogenesis using genome-wide approaches, including employing ChIP-on-chip and microRNA mapping, will reveal molecular controls and the underlying mechanisms in hESC neuronal and cardiomyocyte fate decisions. Unveiling developmental networks during human embryonic neurogenesis and cardiogenesis using novel hESC models will contribute tremendously to our knowledge regarding molecular embryogenesis in human development, thereby, reveal potential therapeutic targets and aid the development of more optimal stem-cell-mediated therapeutic strategies for the prevention and treatment of CNS and heart diseases. The outcome of such research will potentially shift current research to create new scientific paradigms for developmental biology and stem cell research.

MicroRNAs are small, evolutionarily conserved non-coding RNAs that modulate gene expression by inhibiting mRNA translation and promoting mRNA degradation. MicroRNAs act as the governors of gene expression networks, thereby modify complex cellular phenotypes in development or disorders. MicroRNA expression profiling using microarrays is a powerful high-throughput tool capable of monitoring the regulatory networks of the entire genome and identifying functional elements in development in high resolution. To uncover key regulators in human CNS development during embryogenesis, in this Dr. Parsons’ research article, genome-scale profiling of microRNA differential expression patterns during hESC neuronal lineage-specific progression was used to identify novel sets of stage-specific human embryonic neurogenic microRNAs. We found that the prominent pluripotence-associated microRNAs were silenced and microRNAs involved in developmental networks were drastically up-regulated. Our findings suggest that these hESC neuronal derivatives have acquired a neuronal lineage-specific identity by silencing pluripotence-associated miRNAs and inducing the expression of miRNAs linked to regulating human CNS development to high levels, therefore, highly neurogenic in vitro and in vivo. Our study provides critical insight into molecular neurogenesis in human embryonic development as well as offers an adequate human neurogenic cell source in high purity and large quantity for CNS tissue engineering and developing safe and effective stem cell therapy to restore the lost nerve tissue and function. 

Non-Transparent Pre-Application Invented by CIRM Directors – The Biggest Grant Review Loophole for Abuse & Corruption

On the day CA stem cell agency’s governing board proposes dramatic changes in response to IOM report, the darkest process in CIRM grant review procedure remains untouchable. It is called Pre-Application, invented by California Institute for Regenerative Medicine (CIRM) as the safe haven of CIRM directors’ wrong doings, because CIRM would not disclose any information of its pre-applications to the public, not even to IOM. However, understanding CIRM pre-application process is critical for understanding why > $1 billion of CIRM awards have gone into CIRM directors’ own financial interests, not to Prop 71 stem cell research. According to Gilberto Sambrano, who is CIRM Associate Director, CIRM pre-application selection is run by him, CIRM director Pat Olson and 3 or 4 others. They send out pre-applications to 3 outside reviewers they selected in CIRM directors’ favor, most likely CIRM directors’ conflict of interest (COI) alliances, like regular Journal editors do. And those outside reviewers score the word-space-information limited pre-applications based on their own opinions, not any scientific data or scientific merit, NOT like regular Journal or grant reviewers do. There is no procedure in CIRM pre-application to identify abuse & COI. There is no procedure in CIRM pre-application to ensure fair review & competition. And there is no appeal for CIRM pre-application, even it is a flawed grant review, even it has COI. Basically, the reviewers can say whatever they like about CIRM pre-applications and trash their competitors’ research and cell types such as hESC research of Prop 71, because they do not have to provide any scientific evidences to support their opinions, nor concern about any ethics or scientific conduct codes or public opinions or accountability or public scrutiny since no one would know about it, besides the very discouraged & frustrated applicant buried in the pre-application. In our case, the reviewers’ opinions favor trans-differentiation or direct differentiation [<0.5% efficiency, not useful for patients or translatable] of UCSF/Gladstone’s Deepak Srivastava & UCSD Larry Goldstein groups to intentionally give biased comments and low score to Prop71 & hESC research. Those pre-applications favored by reviewers’ opinions would do better to be selected by CIRM directors to recommend to CIRM board, those not favored by the reviewers’ opinions would not be selected, no matter what the scientific data or evidences say & no matter what the Prop 71 says. Just think about who select those reviewers, it is not too difficult to figure out who would be favored by CIRM reviewers and eventually selected by CIRM directors for $ millions awards, which is hard to believe not to be the definition of financial COI. Is Prop 71 written that all CIRM grants should be only scored by 15 members in CIRM board, not decided by a few outside reviewers or CIRM directors using biased non-transparent cheery-picking process? CIRM director Gilberto Sambrano, who seemed not respond to CA stem cell agency’s governing board proposed dramatic changes, was eager to defend CIRM pre-application process & reviewers’ biased comments & scores by agreeing with & elaborating the reviewers’ opinion without any scientific basis, discrediting scientific data/evidences as my own opinion, saying COI cannot be identified & changes cannot be done, discouraging any appeal or even discussion, discouraging any suggestions for fair review/transparency/improvement, then telling me that NIH is doing the same thing too. Although NIH grant review processes contain many loopholes too, at least, NIH allows any applicants to appeal, and the NIH program officials are bound by NIH policy & regulation not to discourage anyone to appeal or they cannot tell anyone not to appeal.

As accounted by Gilberto Sambrano, CIRM non-transparent pre-application process invented by CIRM directors maybe the biggest grant review loophole for abuse & corruption in government funding agencies. It allows CIRM directors to hand pick their own awards with financial COI ties without having to go through fair competition, scientific grant review process, accountability, and public scrutiny. What accounted by CIRM director Gilberto Sambrano would explain that > $1 billion of CIRM awards have gone into CIRM directors’ own financial interests with no Prop 71 scientific merit, hundreds of millions of public funds for stem cell research & cure have gone into stem cell frauds and wastes, the most potential hESC research have been buried in CIRM abusive grant review process, and towards clinical translation of hESC therapy derivatives and medical innovations designated by Prop 71 has not been able to receive a penny from CIRM, and there is zero result from > $1 billion of CIRM awards. According to Prop 71, only the 15 scientist members of the Scientific and Medical Research Funding Working Group shall score grant and loan award applications for scientific merit. There is no such unaccountable pre-application in Prop 71. Pre-application procedure was invented by CIRM directors to counter-act transparency when CIRM began to allow appeal procedure in grant review under public pressure for transparency and accountability. If CIRM really wants to improve transparency and fairness in its grant making and review processes, there are many good & efficient government standards & procedures that they can easily adopt, such as having the applicants to speak and talk about their scientific data and proposal in public meetings, having independent grants appeal officers, having policy & guidelines for reviewers. With ~$ 1 M luxury salary to CIRM president and chair and ~ $ 20 M spending budget from the State, CIRM directors like Gilberto Sambrano would cry about that they could not handle ~ 150 grant applications every time I talk to them. Have we heard CA governor cry about that he cannot handle the state budget? Maybe CIRM should also hire someone who can handle the 150 grant applications to improve its efficiency and transparency as a state government agency. If CIRM cannot even follow and implement Prop 71, if CIRM president Alan Trounson can see no merit in Prop 71 stem cell research, if CIRM directors think they are above the law, it is hard to believe they will adopt any changes and increase transparency of grant making and review processes.

CIRM President Alan Trounson Abuses His CA Top State Official Position in CIRM to Cover Up His COI Alliance and Deny Appeal for Flawed Grant Reviews

California Institute for Regenerative Medicine (CIRM) President Alan Trounson abuses CIRM non-transparent pre-application to cover up his conflicts of interest (COI) alliance using procedural flaw in CIRM grant review, deny appeal for false or biased grant reviews containing anti-Prop 71 anti-hESC research COI comments, and abuses his California top state official position & power in CIRM to block bringing up human embryonic stem cell research (hESC) advances and medical innovations for consideration for public funds against law. Scientific grant review process is supposed to evaluate the scientific merit of applications, such as what is the significance; are there any scientific data to indicate the potential of success of this project; if success, what is the impact. CIRM reviewers’ comments, which are backed up by their top COI alliances in CIRM such as Alan Trounson, are full of biased or false statements, not even near to any standards of scientific grant review involving the consistent application of standards and procedures that produce fair, equitable, informed, and unbiased examinations of grant applications. Maybe, we should also remember that Alan Trounson have denied to bring up hESC grants for consideration against the law, so he could abuse his government official position and power to embezzle CA state funds for his luxury salary and COI alliances with no merit. See our previous posts.

Dear Dr. Trounson,

Could you please give a detailed explanation why you could not see any merit in our application  (please see http://wwwsdrmiorg.blogspot.com & http://www.sdrmi.org/wordpress for editorial, press releases, & our publications for the merit you could not see or clouded by your COI). Maybe, we should also remember that you have denied to bring up hESC grants for consideration against the law, so you could abuse your government official position and power to embezzle CA state funds or public funds for hESC research for your luxury salary and to those who have COI alliances with no merit.

Thanks,

From: Alan Trounson [mailto:ATrounson@cirm.ca.gov]
Sent: Saturday, January 26, 2013 7:44 PM
To: parsons@SDRMI.org; Gil Sambrano
Cc: Jon Thomas; Ellen Feigal
Subject: Re: CIRM ET4 PreApp Review

Gil, I see no merit in this petition. Alan

Directors’ Conflict of Interest Alliance: CIRM Grant Reviews Reveal Some Shocking Anti-Prop 71 Anti-hESC Research Biased Comments Full of Factual Errors against Scientific Evidences

California Institute for Regenerative Medicine (CIRM) grant reviews reveal some shocking anti-Prop71, anti-hESC research, biased comments full of factual errors against scientific evidences, please see most recent example below. We understand there are some directors’ conflict of interest (COI) alliance who are not only not doing any Prop71 stem cell research, but block those who are doing stem cell research to get funding from government funding agencies (e.g., NIH, CIRM), such as Gladstone’s Deepak Srivastava who talks pediatric heart disease in public, then blocks hESC research for pediatric heart disease using his well-connected alliance. It is serious scientific misconducts for those reviewers without scientific integrity use false statements & biases to predispose grants & papers of their COI. We’d like to bring your attention to such procedural flaw in CIRM grant review. Such reviewers abuse CIRM pre-application procedure to cover up their false or biased reviews against scientific evidences, and should be disqualified from reviewing any CIRM grants by making anti-hESC research & anti-Prop71 biased political comments to CIRM applicants. Scientific grant review process is supposed to evaluate the scientific merit of applications, such as what is the significance; are there any scientific data to indicate the potential of success of this project; if success, what is the impact. CIRM reviewers’ comments are full of biased or false statements, not even near to any standards of scientific grant review involving the consistent application of standards and procedures that produce fair, equitable, informed, and unbiased examinations of grant applications. Even we are just scientists or applicants, we strive to voice transparency & fair competition & accountability, not COI & corruption.

Preliminary Application for RFA 12-07

Application number TR4-06762

Project Title (300): Small Molecule-Directed Human Embryonic Stem Cells (hESCs) Cardiomyocyte (CM)-Specific Derivatives for Myocardium Regeneration in Preclinical Models

Objective (1000): Due to the prevalence of heart disease worldwide and acute shortage of human myocardial grafts, there is intense interest in developing hESC-based therapy. However, realizing the potential of hESCs has been hindered by uncontrollable and inefficient multi-lineage differentiation. We found that pluripotent hESCs maintained under defined culture can be uniformly converted into a cardiac specific lineage by small molecule induction. To address unmet medical need in regenerating the damaged myocardium, this proposal uses small molecule directing hESC cardiac lineage-specific differentiation into human CM-specific derivatives at scale, purity, and myocardium regenerative potential adequate for clinical translation. The hESC CM cell therapy products will be characterized and their potential in myocardium regeneration and contractile function restoration will be assessed by transplantation into infracted models. Fulfilling the goal will lead to hESC-based therapy to restore heart function.

Rationale, Significance and Responsiveness (2000): To date, lack of a suitable human cardiomyocyte (CM) source with adequate myocardium regenerative potential has been the major setback in regenerating damaged human heart. Due to the prevalence of heart disease worldwide and acute shortage of donor organs or adequate human myocardial grafts, there is intense interest in developing hESC-based therapy for heart disease and failure. However, realizing the therapeutic potential of hESC derivatives has been hindered by generating CMs from pluripotent cells through uncontrollable and inefficient multi-lineage differentiation. Grafts generated by such hESC-derived CMs have been small, insufficient to restore heart function and functional enhancement not related to regeneration from the grafts. We found that pluripotent hESCs maintained under the defined culture conditions can be uniformly converted into a cardiac specific lineage by small molecule induction. This technology breakthrough enables well-controlled efficiently directing cardiac lineage-specific differentiation of pluripotent hESCs towards human CM derivatives at scale, purity, and myocardium regenerative potential adequate for restoring heart function. With reproducible and scalable production of clinically-suitable hESC CM precursors and CMs, the goal of this project is to provide all necessary evidences of safety and efficacy in preclinical infracted models for moving into IND-enabling preclinical development for tissue and function restoration in myocardium infraction. This proposal meets the scientific merit of Prop 71, adding to CIRM current translation portfolio a novel effective approach for clinical translation of the therapeutic potential of hESC CM derivatives to provide optimal treatment options for incurable end-stage heart failure. Fulfilling the goal of this project will lead to extending healthy life span for millions of patients suffering from end-stage heart failure and reducing the burden of illness and disability of major health problems.

Dear CIRM President and Chair,

We would like to appeal CIRM’s pre-application review for above application for evidences that have indicated a flawed review for lack of appropriate expertise, factual errors, bias or predisposition, and conflict of interest (COI) that have compromised the integrity of scientific review for CIRM. Could you please let me know who to contact and how to appeal a flawed grant review of CIRM, and information about CIRM procedure for appealing a flawed grant review or procedural flaw in CIRM grant review. I just received CIRM announcement yesterday that it seems CIRM proposed dramatic changes in response to IOM report. CIRM must have implemented or will implement their recommendations to ensure CIRM grant review process involve the consistent application of standards and procedures that produce fair, equitable, informed, and unbiased examinations of grant applications to CIRM. Is CIRM grant review process supposed to evaluate the scientific merit of applications, such as what is the significance; are there any scientific data to indicate the potential of success of this project; if success, what is the impact. The reviewers’ comments below are not even near to any standards of scientific grant review. We will appreciate your consideration for our appeal. Please see the procedural flaw in CIRM grant review indicated by the reviewers’ comments below and do not hesitate to contact us should you have any questions.

Comments provided by reviewers: The approach to MI in this application is already represented in CIRM portfolio. It is not at all clear that extent of lineage specific differentiation is the limiting factor in ESC-based cardiac therapies. Advantages of proposed approach releated to rejection issues are not at all developed.
 

Our response: This reviewer’s comment is a factual error. Our approach to MI in this application has not been represented in CIRM portfolio. This proposal meets the scientific merit of Prop 71, adding to CIRM current translation portfolio a novel effective approach for clinical translation of the therapeutic potential of hESC CM derivatives to provide optimal treatment options for incurable end-stage heart failure. CIRM current portfolio does not have any approach that can efficiently regenerate heart muscle (myocardium). CIRM portfolio Cedars-Sinai’s Eduardo Marban & Capricor have no scientific evidences that their adult heart cells can regenerate heart muscle, may produce some smooth muscle or other supporting cells to slow down the dying patient heart muscle cells. CIRM portfolio Joe Wu/Robbin of Stanford U use the traditional multi-lineage differentiation approach to get only <4% heart muscle cells from hESCs, there is no scientific evidence that their cells can regenerate the contractile heart muscle to improve the function. Gladstone/UCSF reprogrammed adult cells or trans-differentiated cells are abnormal, have immnuo-rejection problem and extremely low efficiency (<0.5%) to be any useful in clinics. We have addressed previous reviewers’ biased comments and our effective directed CM differentiation approach by small molecule induction has been fully developed for preclinical studies in this application (see http://wwwsdrmiorg.blogspot.com & http://www.sdrmi.org/wordpress for editorial, press releases, & our publications).  

Comments provided by reviewers: hESC are not clearly translatable cell type.  Direct differentiation is more likely to be approach of the future.  Proposal would be strong if it used partially or fully deprogrammed somatic cells. 

Our response: This reviewer’s comment is biased, anti-Prop 71, anti-hESC research, and a factual error. This project translates advances and medical innovations in hESC research, not pluripotent hESC cell type, which itself cannot be used for therapeutic application. It has been recognized that pluripotent hESCs must be transformed into fate-restricted derivatives before use for cell therapy. This project translates hESC cardiomyocyte (CM) derivatives, including CM precursors & CMs, by direct differentiation of hESCs using small molecule induction, which is more likely to be approach of the future. Human embryonic stem cell (hESC) research holds tremendous potential for tissue and organ regeneration and function restoration. Clinical applications of hESC therapy derivatives provide the right alternate for many incurable diseases & major health problems that the regular mode of treatment cannot. Each single one of those world-wide major health problems cost the health care system or taxpayers more than $10 billion annually. In particular, hESC cardiac derivatives are the only cell source so far that can regenerate the contractile heart muscle (known as cardiomyocytes), vital for cardiovascular repair. In fact, partially or fully deprogrammed or reprogrammed somatic cells are abnormal, & have immnuo-rejection problem and extremely low efficiency (<0.5%) to be any useful in clinics, or partially or fully deprogrammed or reprogrammed somatic cells are clearly not translatable cell type. By the way, Prop 71 is passed by CA voters to fund hESC research, majority of CA voters have said that hESCs are clearly translatable cell type. Did this CIRM reviewer intentionally make comments in CIRM grant review against CA Prop 71 or hESC research, or have any COI with translating hESC research of this CIRM RFA, or telling the public that Prop 71 is not translatable? Such reviewers abuse CIRM pre-application procedure to cover up their false or biased reviews against scientific evidences, and should be disqualified from reviewing any CIRM grants by making anti-hESC research & anti-Prop71 biased political comments to CIRM applicants. We all know we are translated from embryos, not any somatic cells or skin cells. Is this review telling the public that he was translated from some somatic cells, against billions of living evidences? It is shocking to hear such anti-hESC research anti-Prop 71 false or biased comments from CIRM grant reviewers so often.

Comments provided by reviewers: DC: ESC-derived cardiomyocytes generated by directed differentiation under small molecule stimulation, Unmet need: Heart Failure. Weaknesses: Protocols to generate cardiomyocytes from ESC are now widely available.

Our response: This reviewer’s comment is biased. Our novel hESC direct differentiation protocols have been published, are now widely available in public domains, which should be strengthen of this project to CIRM. Only those without scientific integrity like this reviewer, who like to take others’ research for their own private use, would think widely available protocols as weakness to them. Our protocol of hESC CM lineage-specific differentiation by small molecule is novel and ground-breaking, has not been represented in CIRM portfolio (see http://wwwsdrmiorg.blogspot.com & http://www.sdrmi.org/wordpress for editorial, press releases, & our publications). This proposal meets the scientific merit of Prop 71, adding to CIRM current translation portfolio a novel effective approach for clinical translation of the therapeutic potential of hESC CM derivatives to provide optimal treatment options for incurable end-stage heart failure. Conventional protocols to generate CMs from ESC through traditional multi-lineage differentiation are widely available, but have extremely low efficiency (<4%). CIRM current portfolio does not have a approach that can efficiently regenerate heart muscle (myocardium). CIRM Joe Wu/Robbin of Stanford & Geron use the traditional multi-lineage differentiation approach to get only <4% heart muscle cells from hESCs, there is no scientific evidence that their cells can regenerate the contractile heart muscle to improve the function.

From: Gil Sambrano [mailto:GSambrano@cirm.ca.gov]
Sent: Friday, January 25, 2013 5:07 PM
To: parsons@sdrmi.org
Subject: CIRM ET4 PreApp Review

Dear Dr. Parsons:

Thank you for submitting your proposal under the CIRM RFA 12-07: Early Translational IV Awards. After careful consideration, your PreApp was not selected for further review under this RFA.

 The goal of the PreApp process is to identify proposals that are the most responsive to the RFA objectives and likely to be competitive. For this competition we received 151 PreApps and selected about 40 for a full application. The process was designed to handle a large volume of proposals and to ensure a rapid turn-around on the review. Reviewers may provide brief comments that highlight strengths and weaknesses where appropriate. Each application is assigned to 3 independent reviewers and each reviewer assesses approximately 20 PreApps within their area of expertise and scores the applications on a scale of 1 to 100, 100 being the most meritorious. CIRM scientific staff further assesses proposals to ensure that projects meet eligibility requirements and are responsive to the RFA. CIRM invites the most highly ranked and responsive PreApps as determined by the external scientific reviewers and CIRM science officers.

 The summary below shows the final score for your PreApp and comments provided by reviewers.

 We thank you for your interest, and we encourage you to respond to future CIRM initiatives. We look forward to your future applications to CIRM. If you have any questions about the review please feel free to contact me.

 Sincerely,

 Gil Sambrano

Gilberto R. Sambrano, Ph.D.
Associate Director, Review
California Institute for Regenerative Medicine
210 King Street
San Francisco, CA 94107
Phone: 415-396-9103
gsambrano@cirm.ca.gov

SUMMARY OF REVIEW

Overall Scientific Score: 44.00

Comments provided by reviewers:

The approach to MI in this application is already represented in CIRM portfolio. It is not at all clear that extent of lineage specific differentiation is the limiting factor in ESC-based cardiac therapies. Advantages of proposed approach releated to rejection issues are not at all developed. 

hESC are not clearly translatable cell type.  Direct differentiation is more likely to be approach of the future.  Proposal would be strong if it used partially or fully deprogrammed somatic cells. 

DC: ESC-derived cardiomyocytes generated by directed differentiation under small molecule stimulation

Unmet need: Heart Failure

Weaknesses: Protocols to generate cardiomyocytes from ESC are now widely available

Editorial: Human Embryonic Stem Cell Cardiomyocyte Derivatives for Heart Regeneration — The Vital Source for Myocardial Tissue Engineering and Myocardium Repair

San Diego Regenerative Medicine Institute and Xcelthera announce Dr. Parsons’ Editorial, titled “Mending the broken heart – Towards clinical application of human embryonic stem cell therapy derivatives” (doi: 10.4172/2155-9880.1000e116), published in current issue of The International Open Access Journal of Clinical & Experimental Cardiology.

Human embryonic stem cell (hESC) research holds tremendous potential for tissue and organ regeneration and function restoration. Clinical applications of hESC therapy derivatives provide the right alternate for many incurable diseases & major health problems that the regular mode of treatment cannot. Each single one of those world-wide major health problems cost the health care system or taxpayers more than $10 billion annually. In particular, hESC cardiac derivatives are the only cell source so far that can regenerate the contractile heart muscle (known as cardiomyocytes), vital for cardiovascular repair.

Due to the prevalence of heart disease worldwide and acute shortage of donor organs or adequate human myocardial grafts, there is intense interest in developing hESC-based therapy for heart disease and failure. Recent advances and breakthroughs in hESC research have overcome some major obstacles in bringing hESC therapy derivatives towards clinical applications, including establishing defined culture systems for de novo derivation of clinically-suitable stable hESC lines from human blastocysts that have never been contaminated by animal cells and proteins, and direct conversion of such pluripotent hESCs into a large supply of clinical-grade functional human cardiac precursors and cardiomyocytes to be translated to patients for mending the damaged heart. The availability of human cardiomyocyte derivatives in high purity and large quantity with adequate potential for myocardium regeneration will facilitate myocardial tissue-engineering and accelerate the development of safe and effective cell-based therapy for heart disease and failure that affect millions of survivors and so far have no cure. It makes heart disease and failure possible to be the first major health problem to be resolved by clinical translation of the advances of hESC research. Such milestone advances and medical innovations in hESC research provide the only hope to many patients whose life-span is measured in months or years. Further improving policy making, transparency & fair competition of grant review process & government funding agencies, and funding situation for hESC research would drive the advances of medicine to provide new medical treatments for many devastating and life-threatening diseases.