Figure 1: In a personalized approach from  merged Dermal Papillae and  induced pluripotent stem cells (iPSCs) our proprietary and patented HAIROID™️ can be generated. These iPSCs can be differentiated into any human cell or organoid, which in turn can be used for applications like disease modeling, tissue transplanting and drug screening.

INVITROHAIR’ precision medicine approach, is offered to physicians after regulatory approvals!

The below described approach relates to the usage of stem cells for generation of personalized disease models as decision supports for medical doctors. OUR MAIN FOCUS IS THE PRODUCTION OF DE NOVO HUMAN HAIRFOLLICLES FOR TRANSPLANTATION INTO THE SCALP. Beyond that we clearly see applications in drug discovery (together with the pharmaceutical industry) and probably even in in the wellness / beauty sector. However, these aspects are discussed in other sections of our offerings.

From patient samples to tissue models

The basis for all models developed by INVITROHAIR are personalized induced pluripotent stem cells (iPSCs). For generating this cells INVITROHAIR can start with any kind of somatic cells. However, we prefer to work with FUE extracted (30) hairfollicles or skin Fibroblasts (Yu et al., 2007). Alternatively also protocols for blood cells are well established (Zhou et al., 2015) furthermore protocols from urine are developed as well (Beda et al., 2012). We believe the sample collection from urine donations will become increasingly important.

„Rationally, clinicians and researchers have relied on a skin biopsy or blood extraction as relatively accessible supplies for in vitro cell expansion and biological studies. Perhaps surprisingly, limited attention has been given to a totally noninvasive source, urine, which eliminates the discomfort associated with other procedures. This may arise from the perception that urine is merely a body waste. Yet, the analysis of urine is a longstanding fundamental test for diagnostic purposes and nowadays there is growing interest in using urine for detecting biomarkers. In addition, recent work including ours, reinforces the idea that urine contains a variety of viable cell types with relevant applications.“

Starting from iPSCs we specialized on the generation of denovo human hairfollicle for Test and Transplantation . However, also organoids for other tissues as well as “connected organoids”  like skin are conceivable.

Importantly, all our activities are in full compliance with the existing national and European legislations (e.g.Helsinki Declaration, article 19 of Regulation (EU) No 1291/2013, Universal Declaration on the Human Genome and Human Rights of UNESCO of 11 November 1997). Furthermore, we confirm that guidelines defined by the WHO Expert Committee on Biological Standards (ECBS) and the NIBSC in the development of reference standards will be duly adhered to. The appropriate facilities for the handling of human cells are available. We only generate iPSCs after approval by the responsible local ethics committees. All donor related information is pseudo-anonymised, thereby the highest level of data protection is guaranteed. The individual iPSCs will be identified by a specific code number. All data generated in this project will solely be entered only on secure password protected computers.

What is P4 medicine?

P4 Medicine is Predictive, Preventive, Personalized and Participatory. Its two major objectives are to quantify wellness and demystify disease.

  • P4 medicine is the clinical face of systems medicine.
  • P4 medicine will make hairfollicles a diagnostic window for viewing health and disease for the individual.
  • P4 medicine will provide new approaches to personalized drug target discovery and autologous tissue transplants.
  • P4 medicine will drive profound economic, policy and social changes.

INVITROHAIR focuses on certain aspects of the P4 medicine revolution. The emphasis is clearly on advanced disease modeling to provide personalized recommendation to medical doctors AND THE TRANSPLANTATION OF HAIRFOLLICLES TO THE HUMAN SCALP. In order to achieve that INVTROHAIR  is building on its strong competences in stem cell technologies.

Some years ago, the proposition that healthcare is evolving from reactive disease care to care that is predictive, preventive, personalized and participatory was regarded as highly speculative. Today, the core elements of that vision are widely accepted and have been articulated in a series of recent reports by the US Institute of Medicine. Systems approaches to biology and medicine are now beginning to provide patients, consumers and physicians with personalized information about each individual’s unique health experience of both health and disease at the molecular, cellular and organ levels. This information will make disease care radically more cost effective by personalizing care to each person’s unique biology and by treating the causes rather than the symptoms of disease (Flores et al., 2013).

We predict two mega-trends in health care in the future:

1. Medical doctors will use patient specific / personalized information and models in clinics and hospitals to make efficient (cost effective as well as function) diagnosis and treatments.

2. Patients as well as healthy individuals will want to have personalized models and information’s to make their lives healthier and more productive. 

Generation of personalized, patient specific, stem cells

Our approach is described in our patent as follows:
The present disclosure relates to a bioengineering process to derive hair follicles in vitro from the in vitro disposition and differentiation of pluripotent stem cells and dermal papilla stem cells. Whereas we’re usually merging Dermal Papillae cells (DPSC) with autologous induced pluripotent stem cells (IPSC).

Induced pluripotent stem cells (also known as iPS cells or iPSCs) are a type of pluripotent stem cell that can be generated directly from adult cells. The iPSC technology was pioneered by Shinya Yamanaka’s lab in Kyoto, Japan, who showed in 2006 that the introduction of four specific genes encoding transcription factors could convert adult cells into pluripotent stem cells. Yamanaka was awarded the 2012 Nobel Prize along with Sir John Gurdon "for the discovery that mature cells can be reprogrammed to become pluripotent."

Pluripotent stem cells hold great promise in the field of regenerative medicine. Because they can propagate indefinitely, as well as give rise to every other cell type in the body (such as neurons, heart, pancreatic, and liver cells), which includes also the generation of organoids (mini-organs) (Figure 1 showcases cell therapies).

INVITROHAIR has the abilities to use human samples (preferably hairfollicle and skin biopsies) to isolate DPSC and generate iPSCs and to differentiate them further in somatic cells or organoids. Importantly, the whole approach is fully personalized.

Application of stem cells and their derivates for the Patient’s wellbeing

After isolating Dermal Papillae cells and generating induced pluripotent stem cells, in consultation with the medical doctor who knows the patient, depending on the exact question, disease, treatment status etc., several applications can be done. Some examples are giving below:

Predicting disease and risk factors - Genome sequencing

From the obtained stem cells genomic information (DNA) will be isolated and this will be used for sequencing. Based on the genetic information risk factors e.g. for various Alopecia diseases will be identified. Furthermore, the carrier status* for more than 40 diseases (including Cystic Fibrosis or Gaucher Disease) can be determined. Also some wellness (e.g. Alcohol Flush Reaction or Lactose Intolerance) and trait related conditions can be determined.

* A carrier is not suffering from the disease himself but they can pass a variant to their children.

Models for Alopecia

INVITROHAIR has developed stem cell derived models that resembles the human hair . Particularly we have focused on models Alopecia disease and we are in the process of developing further models for other hairloss diseases.

Based on the stem cells generated from patients we can generate this kind of hair models (Figure 2) and investigate whether disease associated phenotypes are detected. Typically such an approach would only be done in cases where the disease has been diagnosed. Currently several new drugs against these devastating diseases are in clinical trials and they are expected to become available soon. We could pre-test these substances directly on the personalized organoids with our INSILICO screening and OOC devices, and inform the medical doctor which simulation led to the most favourable outcome.

Figure 2: A human de novo hair organoid, derived from iPSCs and merged DPSC is shown. 

Beyond…

Naturally, since we discuss personalized approaches only some examples have been described. The exact disease pathology that should be addressed will determine the approach.

Furthermore, research and development will make these models even more complex in the future. This will certainly cover also the inclusion of the immune system in organoids as well as very complex multiple organ  models (hair-on-a-chip).


Figure 3: Multiple OOC device  developed by the OOC pioneer Tissuse. 


References

Yu J., Vodyanik M.A., Smuga-Otto K., Antosiewicz-Bourget J., Frane J.L., Tian S., Nie J., Jonsdottir G.A., Ruotti V., Stewart R., Slukvin I.I., Thomson J.A. (2007) Induced pluripotent stem cell lines derived from human somatic cells. Science 318(5858):1917-20

Zhou H., Martinez H., Sun B., Li A., Zimmer M., Katsanis N., Davis E.E., Kurtzberg J., Lipnick S., Noggle S., Rao M., Chang S. (2015) Rapid and Efficient Generation of Transgene-Free iPSC from a Small Volume of Cryopreserved Blood. Stem Cell Rev. 11(4):652-65

Yoshioka N., Gros E., Li H.R., Kumar S., Deacon D.C., Maron C., Muotri A.R., Chi N.C., Fu X.D., Yu B.D., Dowdy S.F. (2013) Efficient generation of human iPSCs by a synthetic self-replicative RNA. Cell Stem Cell 13(2):246-54
C. Benda (&) T. Zhou X. Wang W. Tian D. Pei M. A. Esteban
Key Laboratory of Regenerative Biology, Chinese Academy of Sciences, SC.

Benda T. Zhou X. Wang W. Tian D. Pei M. A. Esteban
Guangdong Provincial Key Laboratory of Stem Cells and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Guangzhou 510530, China

J. Grillari R. Grillari-Voglauer
Aging and Immortalization Research, J. Grillari R.