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Novel Cells for Organ Repair

Periodic Reporting for period 4 - PROMETHEUS (Novel Cells for Organ Repair)

Período documentado: 2020-02-01 hasta 2020-10-31

As western populations age, we face new challenges to diagnose, prevent, and treat degenerative diseases in which our bodies can no longer repair tissue damage accrued due to age or injury. The natural healing response relies on the replenishment of tissue cells by local resident precursor cells that can give rise to all necessary cell types of a given tissue. As we age, these “repair cell” populations naturally decline, or, as in the case of the nervous system, they are present in very limited quantities from the very start. Aging, from a cellular perspective, is the inability to maintain healthy populations of functioning cells in a wide variety of tissues. Society could counter tissue decline by finding new ways to replenish local repair cell populations, which are capable of maintaining and refreshing tissue function from within their natural environments. In the nervous system, boosting these precursors has already proven to augment healing responses and cognitive output in mice and thus promises to be a possible strategy to counter cognitive decline in the human brain as well.

Our objective in this project is to identify cocktails of factors that are capable of converting normal tissue cells into such repair cells while these cells reside in their local microenvironment in vivo. We would like to avoid generating pluripotent stem cells in these tissues as they have proven to bear a high tumor risk. Thus, we are aiming to generate multipotent repair cells which have a much lower tumorogenicity and augment or reestablish the natural healing response in aged or compromised tissues. Finding cocktails of such factors that function in human tissues requires testing many different combinations of candidate factors. This requires a robust experimental test system that emulates key tissues of the body with their many interdependent and interacting cell types. The emerging scientific sub-field of organoid biology allows us to build small scale tissues (organoids) with a size of 1-3 mm in the lab and test our factor combinations in these model systems. We are planning to identify cocktails that are capable of turning normal tissue resident (somatic) cells into repair cells in the nervous system, the germ line, and the hematopoietic system to counter key areas of age or degeneration-related decline.
Since starting this project, we made key advancements towards our projected goals in several organ systems:

Neural System

We have produced neural organoids that comprise a variety of key cell types in complex, tissue-like three-dimensional cell culture. We have further standardized and automated the production of these organoids, so that we can generate many thousands of these tissue-surrogates for parallel testing of repair-cell induction factors. We have also begun tackling the challenge of reading out key biological data from these large-scale and heterogeneous cell aggregates. Organoids’ size and tissue density prevents normal imaging techniques from penetrating more than the very outside layer of cells by light scattering and absorption. This means processes that occur in the center of the organoids are hard to detect. By optimizing clearing protocols that render organoids much more transparent after treatment, we could boost visibility to ten times their previous depth, thus significantly enhancing our analysis capability for detecting newly generated repair cells in our organoid test system.

Germline and hematopoietic system

We have tested a number of factor and media combinations for their ability to generate germline precursor cells and have identified a successful combination. The resulting cells express key markers of the early germline and are promising candidates for further evaluation in tissue-like environments.
Progress beyond the state of the art

To our knowledge, no one has demonstrated the ability to generate human neural organoids in an automated system. Neurons are post-mitotic, and thus human neural tissue is not generally available for large scale screening applications such as in drug development or toxicity testing. These essential research steps have so far been carried out with animal models. There is a large biological gap between animal models and the human physiology, especially in issues pertaining to the nervous system. A fully scalable, automated approach for generating human brain-tissue-surrogates could bridge the gap between in vitro and in vivo work by providing a complex human cell-based test system that recapitulates key developmental and health aspects of the human brain in a dish. So far, organoid production requires extensive manual labor, thus limiting the scope of organoid-based experiments. With our automated approach, we open the door to use artificial human brain tissue in large scale high throughput screening campaigns as they are used in the pharmaceutical industry or in chemical toxicity testing.

Socio-economic impact and societal implications

Long term, the potential socio-economic impact is very large. If we succeed in rekindling or augmenting the body’s own tissue-resident repair function, we will fundamentally change the way we approach medical treatment of aging or chronic degenerative decline. By addressing this question in a variety of key tissues, we potentially counter age-related ailments in the nervous system, the reproductive system, and the blood stream. In the long run, maintaining inherent tissue repair function could lead to longer life spans with a much higher quality of life especially in the older population. The societal impact for quality of life for patients, for the cost of care, and for the life of relatives and care givers should not be underestimated.

Mid-term, our pioneer protocols for automating organoid production can turn the next page in drug- and toxicity testing. Over time, it becomes more evident that animal models are differing in key biological aspects and thus cannot fully emulate human biology even under the best conditions. Harnessing the power of cellular self-organization, organoid technologies and human 3D-cell culture are bound to become the next generation technology for drug screening and tox evaluation by emulating the rich interplay of various cell types in the complex arrangements of tissues. Tremendous progress has been made in this field in the last few years, and we are at the forefront of enabling large scale screening campaigns for diseases that are uniquely human and could not be addressed with animal models so far. Incidentally, establishing drug and tox-screening in human organoid systems could also significantly reduce the number of animals necessary in early stage clinical testing as toxic compounds can be excluded early in drug and safety testing pipelines.
Detailed views of automated midbrain organoids