Goal 3: Advance Translational Research

Regenerative Medicine 2.0 in Heart and Lung Research - Back to the Drawing Board

Stem cell therapies have been quite successful in hematologic disease but the outcomes of clinical studies using stem cells for cardiopulmonary disease have been rather modest. Explanations for this discrepancy such as the fact that our blood has a high rate of physiologic, endogenous turnover and regeneration whereas these processes occur at far lower rates in the heart and lung. Furthermore, hematopoietic stem cells ...more »

Submitted by (@jalees)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Critical Challenge (CC)

Details on the impact of addressing this CQ or CC :

Some barriers to successfully implementing cardiopulmonary regeneration include the complex heterogeneous nature of the heart and lung.

 

Hematopoietic stem cells can give rise to all hematopoietic cells but the heart and lung appear to contain numerous pools of distinct regenerative stem and progenitor cells, many of which only regenerate a limited cell type in the respective organ. The approach of injecting one stem cell type that worked so well for hematopoietic stem cells is unlikely to work in the heart and lung.

 

We therefore need new approaches which combine multiple regenerative cell types and pathways in order to successfully repair and regenerate heart and lung tissues. These cell types will likely also require specific matrix cues since there are numerous, heterogeneous microenvironments in the heart and lung.

 

If we rethink our current approaches to regenerating the heart and lung and we use combined approaches in which multiple cell types and microevironments are concomitantly regenerated (ideally by large scale collaborations between laboratories), we are much more likely to achieve success.

 

This will represent a departure from the often practiced "Hey, let us inject our favorite cell" approach that worked so well in hematologic disease but these novel, combined approaches targeting multiple endogenous and/or exogenous regenerative cells could fundamentally change our ability to treat heart and lung disease.

Name of idea submitter and other team members who worked on this idea : Jalees Rehman

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Goal 2: Reduce Human Disease

Stem Cell Immunology

We now can create critical cell types like cardiomyocytes etc. from stem cells. Additionally, we are learning the rules of using these cells to rebuild tissues. A major gap in our knowledge relates to the immunobiology of these cells. Lessons from transplantation medicine are only partially applicable, because solid organs are more complex and likely more immunogenic than defined cell populations. How does the immune ...more »

Submitted by (@murry0)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

We now can generate large quantities of critical cell types whose deficiencies underlie many chronic diseases like heart failure. This breakthrough brings us to the next-level impediment: the immune system. While induced pluripotent stem cells have the potential to obviate rejection, in practical terms this is cost-prohibitive: It will cost huge amounts of money to produce and qualify a single patient's cell dose. Moreover, human cardiomyocytes are potent when given to infarcted hearts in the acute or sub-acute phase of infarction, but they have no benefit with chronic heart failure. The 6 months required to produce iPSC-cardiomyocytes precludes their autologous use for myocardial infarction.

 

We need an off the shelf cell therapy product for myocardial infarction that can be mass produced and qualified for large numbers of patients. This means an allogeneic product is necessary. Identifying the immune response to cardiomyocytes or other cell products will teach us how to precisely immunosuppress the patient, thereby minimizing complications, or alternatively, how to engineer the cells so as to avoid immunogenicity in the first place.

 

Lessons from the study of cardiomyocyte transplantation could extend to dopamine neurons, pancreatic beta-cells, retinal cells, myelinating cells and many other areas that cause common chronic disease.

Feasibility and challenges of addressing this CQ or CC :

We know a great deal of transplant immunology from hematopoietic stem cell transplantation (graft versus host) and from solid organ transplantation (host versus graft). There are good mouse and large animal (including non-human primate) models of stem cell differentiation and organ transplantation. This offers low hanging fruit where, in perhaps 5 years, we could discern the critical similarities and differences between transplanting stem cell derivatives and organ or marrow transplantation. These studies will inform clinical trials of allogeneic human stem cell derivatives that will be underway by then.

 

Success in this area will require bringing together researchers interested in stem cell biology and transplant immunology. A properly resourced RFA from NIH could be just the thing needed to promote this interaction.

Name of idea submitter and other team members who worked on this idea : Charles Murry, MD, PhD

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Goal 2: Reduce Human Disease

Lung progenitors and disease

What is the role of lung stem/progenitor cells in disease?

Which diseases involve stem cell defects?

Submitted by (@nhlbiforumadministrator1)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Name of idea submitter and other team members who worked on this idea : NHLBI Staff

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Goal 3: Advance Translational Research

Can hair follicle stem cells be transformed into new cells or organs?

Dr. Cotsarelis of the Univ. of Pennsylvania identified the bulge area of the hair follicle, which is now thought to contain the hair's stem cells. These cells would seem to be readily available and unique to an individual person. Can further work be done to transform these cells into now only hair cells but other organ tissues?

Submitted by (@info00)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

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Goal 2: Reduce Human Disease

Lung cell stimuli responses

What alterations in respiratory epithelia in response to environmental / external insults are irreversible and lead to disease onset or progression?

Submitted by (@nhlbiforumadministrator1)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Name of idea submitter and other team members who worked on this idea : NHLBI Staff

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Goal 1: Promote Human Health

Endoglin Regulates biolgy and signal transduction in vascular smooth muscle cells

Why loss of endoglin causes HHT is not known. Endoglin is expressed by vascular smooth muscle cells and endothelial cells.

What is the role of endogin on vascular smooth muscle cells and why its loss contributes to HHT and other vascular malformations

Submitted by (@mariannes.clancy)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

Vascular smooth muscle cells wrap around arteries and control their diameter.

Name of idea submitter and other team members who worked on this idea : Marianne Clancy MPA, Chris Hughes PhD

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Goal 3: Advance Translational Research

Spinal Cord Injury: hype, unmet promises, and misery which does not need to be

Research to "fix" spinal cord injury in humans, has been insanely hyped, rare in reality, and very disappointing in its clinical applicability to human patients. After a parade of rat models, mouse models, cat models, dog models, African green monkey models, pig models, guinea pig models, hamster models, rabbit models, gerbil models, etc. one wonders whether most researchers or funders will ever have any interest in ...more »

Submitted by (@mgwmgw)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Critical Challenge (CC)

Details on the impact of addressing this CQ or CC :

So, how about we put a moratorium on FDA approval of all research related to a cure for spinal cord injury when done by any persons or organizations who have not published every single one of their past experiments in the time required, and for any research which involves other species than humans.

 

Also, how many different ways of creating stem-like cells do we need? Let's stop creating stem-like cells and start applying the ones we have to human patients.

 

How about spending the animal model money instead on improving the quality of life for people living with disabilities. Let us start with actually enforcing the ADA on all new enough buildings.

 

When we make technology for doctors to use, we consult doctors. When we make technology for teachers to use, we consult teachers. When we make technology for disabled people to use… we consult insurance companies, and medical professionals who are not and have never been disabled. We fail to apply the most basic usability testing to the tools which disabled people must use. For example, has any wheelchair designer tried to propel a manual wheelchair uphill on wet grass? How about across a cobblestone street? or down a normally bumpy sidewalk? Now imagine that your butt has atrophied and you are sitting on your hip bones. How painful would that be? Now remember that pressure sores resulting from this bad design can be fatal, and then tell me why we do not take this more seriously.

Feasibility and challenges of addressing this CQ or CC :

The misery which does not need to be is not a new idea: http://badcripple.blogspot.com/2015/01/obsession-with-walking.html

 

Let's get the price of tools for disabled people down to the point where most patients can really afford them, or where the insurance can actually cover them. Let's get exoskeletons price-competitive with wheelchairs, for example, instead of using them to make soldiers able to carry heavier packs in war.

Name of idea submitter and other team members who worked on this idea : Mary-Anne Wolf (inspired by the Bad Cripple blog of William Peace and by the Wheelchair Driver website forum)

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Goal 2: Reduce Human Disease

Do we yet know all of the Resident Cellular Components of the Human Lung?

The DLD, NHLBI workshops conducted and published (Reference 1, 2, 3) had as their purpose to stimulate research that would identify still obscure or novel cellular components of the human lung to determine cell function in promoting respiratory tract development and in health that contributes to disease, so that better therapy might result. With robust technologies now available, especially genomic advances, how much ...more »

Submitted by (@nhlbiforumadministrator1)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

To completely understand how the human lung responds and reacts to inhaled or aspirated particles, microbes, and environmental antigens, etc.; then initiates innate and/or acquired adaptive immunity; or creates a milieu wherein cancerous cells that have travelled to the lung can establish metastatic sites, we must identify, characterize through special phenotyping and cellular function, and isolate for ex vivo study the still understudied and unknown properties of a sizable number of the 40 resident cell types in the human lung.

 

Knowledge about all the resident cells in the human lung and their functions should enhance understanding of the respiratory tract in health and disease.

 

References:

1. Needs and opportunities for research in hypersensitivity pneumonitis.

Fink JN, et. al.

Am J Respir Crit Care Med. 2005 April 1;171(7):792-8. Review.

 

2. The mysterious pulmonary brush cell: a cell in search of a function.

Reid L, et. al.

Am J Respir Crit Care Med. 2005 July 1;172(7):136-9. Review.

3. Resident cellular components of the human lung: current knowledge and goals for research on cell phenotyping and function.

Franks TJ, et. al.

Proc Am Thorac Soc. 2008 Sep 15;5(7):763-6. Doi: 10.1513/pats.200803-025HR.

Feasibility and challenges of addressing this CQ or CC :

Technologies seem available.

Name of idea submitter and other team members who worked on this idea : Herbert Y. Reynolds, M.D.

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Goal 3: Advance Translational Research

Translational Research for HIV/AIDS and HLB Health and Diseases

What are the best inroads for the NHLBI to support innovative approaches in the next 5-10 years, especially blood cell therapies based on hematopoietic stem cell and novel gene therapy approaches to control or even cure HIV infection?

Submitted by (@nhlbiforumadministrator)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

HIV control or possibly even HIV cure could result from developing novel cell therapies, especially hematopoietic stem cell (HSC) transplants, and might also result from early use of antiretroviral therapy in acutely HIV-infected individuals.

• Transplantation of HSC including engineered cells has the potential to eradicate HIV reservoirs for HIV cure: the Berlin patient treated with HSC transplant remains free of HIV and is still the only patient cured of HIV infection as of today;

• Identification of acute HIV infections through routine blood donor screening and early anti-retroviral therapy for identified HIV-infected donors can limit or even prevent the establishment of HIV reservoirs.

Feasibility and challenges of addressing this CQ or CC :

• The Berlin patient has provided the proof of concept that HIV infection can be eradicated, that is, sterilizing cure can be achieved, through HSC transplantation in combination with other therapies;

• Recent studies have shown that early identification of HIV infection and treatment of infected individuals with anti-retroviral therapy as soon as possible can significantly limit the size of the HIV reservoirs even if such early treatment may not be able to completely prevent the establishment of HIV reservoirs; routine blood donor screening for both anti-HIV antibodies and HIV RNA among blood donors offers unique opportunities to identify acute HIV infections.

 

 

For HIV cure, the challenges include:

 

• Generation of HIV-resistant HSCs in adequate quantity for transplantation;

 

• Efficiency of homing and expansion of HIV-resistant HSC transplants;

 

• Efficiency in replacing HIV-infected cells, including CD4+ resting cells as the major HIV reservoirs, with HIV-resistant HSCs following transplantation;

 

• Efficiency in immune reconstitution by HSC transplants;

 

• Safety of HSC transplantation with needed GVHD to eliminate HIV-infected resting T cells while avoiding irreversible damage to the host.

Name of idea submitter and other team members who worked on this idea : NHLBI Staff

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Goal 2: Reduce Human Disease

Engineered ECM for heart repair

Utilizing advances in nano, bio, tissue and related engineering technologies to construct cardiac ECM for heart repair.

Submitted by (@nhlbiforumadministrator1)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Critical Challenge (CC)

Details on the impact of addressing this CQ or CC :

Will advance cell and gene based therapeutics for cardiac repair. Despite promise, efficacy of cell based therapies remains largely unproven and this may in part be due to poor understanding of cell-ECM interactions. Research efforts in engineering cardiac ECM have the potential to greatly advance such therapeutic approaches.

Feasibility and challenges of addressing this CQ or CC :

This research field is ripe for experimentation and testing.

A major thrust of recent efforts in repairing cardiac injury has focused on cell therapies. However, since the ECM provides the necessary scaffold for the cells it is important to consider the cell-ECM interactions when utilizing these approaches.

 

Will require multi-disciplinary expertise.

Name of idea submitter and other team members who worked on this idea : NHLBI Staff

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Goal 2: Reduce Human Disease

Harnessing Lung Regenerative Capacity to Improve and Increase Donor Lungs for Transplantation.

Using knowledge of matrix biology and lung development, what are useable methods to modify cadaveric donor lungs to provide a durable, effective organ replacement therapy?

Submitted by (@nhlbiforumadministrator)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

A major advance in this area will increase the number of donor lungs available for lung transplantation

Feasibility and challenges of addressing this CQ or CC :

A number of stem and progenitor cells involved in lung repair and regeneration have been identified. Targeting them for expansions in damaged donor lungs may turn these damaged lungs into healthier lungs that can then be used for lung transplant safely.

Most of the donor lungs are not suitable for lung transplantation because the premorbid conditions of the donors often also damaged the lungs. Bioreactors have been used to “rehab” these damaged lungs and optimizing the ex vivo condition in these bioreactors may accelerate the lung repair process.

Name of idea submitter and other team members who worked on this idea : NHLBI Staff

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Goal 1: Promote Human Health

Funding of Stem Cell/Lung Regeneration Research

How to "cure" a chronic, incurable disease - A potential giant step in saving the lives of many thousands of Americans, and potentially millions worldwide, who are afflicted with COPD, the third leading cause of death in the U.S. The financial effect of COPD in the United States alone is well over $50 billion per year. It is estimated that some 30 million Americans have COPD, which of course means that at least that ...more »

Submitted by (@jimandmarynelson)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Critical Challenge (CC)

Details on the impact of addressing this CQ or CC :

COPD is chronic and presently incurable. Although it sickens and disables nearly 30 million Americans, and kills 140,000 of them each year, the only "cure" is a lung transplant. Due to the scarcity of organ donors and the requirements that lungs be removed from the donor in a hospital setting, only about 1,400 lung transplants are performed in the Unites States each year. Unfortunately, transplants are fraught with complications, side effects, and potential rejections, and on the average, add only about 5 years to the life of the recipient. The best potential solution lies with the stem cell and lung regeneration research that is presently occurring at a few centers around the country. Ideally, the re-engineered lungs would be composed of the patient's own stem cells, eliminating a great many of the current transplant issues.

Feasibility and challenges of addressing this CQ or CC :

Research is presently in process on construction or reconstruction of human organs. There has been success in creating some of the simpler organs, such as the esophagus and bladder, and a Medical Center in Galveston has implanted re-engineered lung is a pig. As of my latest conversation with the lead Doctor on the project, results so far are promising.

There is general agreement among the researchers with whom I have communicated that we are between 5 and 20 years away from human trials of re-generated lungs using the patient's own stem cells, but more funding means more research which means more possibilities of the saving of lives.

Name of idea submitter and other team members who worked on this idea : Jim Nelson - COPD Foundation MASAC/CAC/BOARD Committee Member

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