The Science of Fibroblast Cell-Based Therapies

Fibroblast Technology

what are fibroblasts?

There are only two cell types in the human body that can regenerate tissue and organs: stem cells and fibroblasts.

Fibroblasts comprise the main cell type of connective tissue, possessing a spindle-shaped morphology, and produce and maintain the extracellular matrix responsible for the structural integrity of tissues and organs. Fibroblasts also play an important role in immune modulation, in addition to the tissue remodeling and proliferative phases of wound healing, resulting in the deposition of the extracellular matrix.

Fibroblasts greatly outnumber stems cells 

As one of the most abundant cells in the human body, present in all tissues and systems, fibroblasts have many of the same characteristics as stem cells, but lack the sourcing, isolation, and culturing limitations that stem cells have.

why use fibroblasts?

Easy to Source

Excess tissues from surgeries can serve as a primary source of allogenic fibroblasts. A single dermal punch from a patient can provide a sufficient source of autologous fibroblasts for most clinical applications.

Better Isolation

Isolation of fibroblasts from tissues is more streamlined and straightforward. Fibroblasts are more robust than stem cells, have a significantly lower doubling time averaging 16-24-hours, and are stable for up to 15 passages.

Cost Effective Culturing

The culture media requirements for expanding and maintaining fibroblasts are less stringent than stem cells. They do not require costly additives compared to stem cells, reducing the complexity and cost of manufacturing high-quality and consistent batches of fibroblasts.

1

CNS Disorders
(Multiple Sclerosis)
The results of our pre-clinical and safety-centered limited clinical trial data to treat and cure autoimmune diseases are promising. Read more

2

Thymus
As we age, key organs in the body like the thymus decline. We are currently exploring the potential capabilities of fibroblasts to improve and extend the productive life of the thymus through fibroblast cell-based therapies. Read more

3

Spleen
As we age, key organs in the body like the spleen decline. We are currently exploring the potential capabilities of fibroblasts to improve and extend the productive life of the spleen. Read more

4

Skin (wound healing)
Fibroblasts naturally play an integral part of the complex and intricately orchestrated wound healing process that involves multiple systems and cells. Read more

Fibroblasts share many of the characteristics of stem cells, including differentiation and immune modulation.

Fibroblasts share many of the characteristics of stem cells, including differentiation and immune modulation.

Our studies have proven fibroblasts to be more effective and more potent than stem cells in regeneration and immune modulation. As the most common cell in the human body, fibroblasts are easier to source, culture, and differentiate into many different cell types, including chondrocytes, adipocytes, cardiomyocytes, hepatocytes, osteocytes, and epithelial and endothelial cells making them an ideal candidate for use in clinical applications involving tissue regeneration. In addition, they are easier to maintain, and less prone to damage with cold-chain shipping logistics.

fibroblast benefits

Fibroblast cell-based therapies will be more accessible to patients, more effective, and less expensive than stem cells.

As our clinical work moves into human trials, we believe FibroBiologics will prove that allogeneic and autologous fibroblast cell-based therapy is the most promising opportunity to treat chronic diseases that modern medicine has seen in many generations.

Therapeutic Areas

CNS Disorders (Multiple Sclerosis). Multiple Sclerosis (MS) is a T cell-mediated autoimmune disorder targeting the myelin sheath, which affects about one million individuals in the United States, and around 3 million individuals worldwide. While the FDA has approved a number of small molecules and monoclonal antibodies for reduction of the relapse rate, reduction in the severity of relapse, and reducing the rate of progression of MS, all carry short and long term side effects that can impact the quality of life and overall health of the patients. Unfortunately, as of yet, there are no minimal-side effect therapies or cures for MS in the approval pipeline. While publications and clinical trials indicating the use of mesenchymal stem cells (MSCs) for autoimmune disorders are abound, publications utilizing fibroblasts for autoimmune diseases, which share many of the characteristics of MSCs, have been few and far between. Like MSCs, fibroblasts have the capacity for differentiation into several other cell types, can be prepared to be tolerogenic, have been studied extensively for wound healing, and have demonstrated tissue regeneration activities. However, unlike MSCs, HDFs are more abundant, are easier to source, have a faster doubling rate, and are far cheaper and easier to culture. In our quest to better understand the potential of HDFs in treating MS, we carried out extensive in vitro and in vivo pre-clinical studies of tolerogenic HDFs in the experimental autoimmune encephalomyelitis (EAE) animal model of multiple sclerosis. Our pre-clinical results, which we will present at this meeting, demonstrate that tolerogenic HDFs can suppress pathogenic T cell activation, stimulate T regulatory (Treg) cell expansion, inhibit dendritic cells (DC) maturation, stimulate oligodendrocyte expansion and myelin protein expression. In addition, our results indicated that administration of HDFs in the EAE model of MS led to a Treg-dependent disease inhibition that was significantly better than adipose or bone marrow-derived MSCs. Additionally, our comparison to adipose and bone marrow-derived MSCs indicated a clearly significant improvement in immune modulation with tolerogenic HDFs. The promising results of our pre-clinical study led to our small scale 16-week MS clinical trial to test the primary safety for a single-dose infusion of tolerogenic HDFs into four relapsing-remitting and one secondary progressive MS patient. The study’s primary outcome was safety, and a physician monitored the patients during the infusion and up to 4 hours post-infusion for any adverse events. No adverse events were noted during the study. We also monitored the patients using CBC, blood chemistry, and electrocardiogram for any changes during the study period. Safety data collected prior to the single-dose tolerogenic infusion was compared to safety data collected at the 8 and 16 week monitoring period. Our results indicated a strong correlation (Pearson r > 0.99) for CBC, blood chemistry, and electrocardiogram data for all patients when comparing pre-infusion test results to the 8-week and 16-week follow-up results. As a secondary outcome, we also looked at efficacy by utilizing routinely utilized MS neurological tests such as Paced Auditory Serial Addition Test (PASAT), Nine-Hole Peg Test, Timed 25 ft. Walk Test, Expanded Disability Status Scale determination, and Gadolinium Enhanced MRI of the brain and cervical spinal cord. Our secondary outcome efficacy data demonstrated a clinically significant improvement in PSAT and Nine-Hole Peg Tests. However, our short duration study of 16 weeks did not indicate any improvement or deterioration in the Timed 25-foot Walk Test or EDSS. Gadolinium Enhanced MRI results of the patients also did not indicate any change in MRI as compared to pre-infusion baseline. Additionally, Gadolinium Enhanced MRI at the end of the 16-week study period did not indicate any new lesions. We are very encouraged by the promising results of our pre-clinical and safety-centered limited clinical trial data for the single-dose infusion of tolerogenic HDFs1. We are in the process of submission for an IND to further study the safety and efficacy of various concentrations of HDFs and the impact of multiple-dose infusion of HDFs during an eighteen-month study period.
Thymus. Fibroblasts produce an environment that influences T regulatory cell migration, proliferation, and activity to ensure immunotolerance1. One of the key organs of the immune system is the thymus.  It serves a vital role in T cell maturation and selection, elimination of self-reactive cell, establishment of central tolerance, and T cell migration to recognize a wide range of pathogens. A variety of cells have been identified inside the thymus. These include, epithelial cells, thymocytes, dendritic cells, macrophages, B lymphocytes, myoid cells, endothelial cells, and fibroblasts2-5.  With age, the thymus declines in functionality through a process referred to as thymus involution. Publications have indicated that process of involution enhances regulatory T cell (Treg) generation which leads to increased susceptibility to pathogen infections, tumors, and autoimmune diseases6. Thus, there is a need for improving and extending the productive life of the thymus through cell therapy, which this disclosure accomplishes, in some embodiments, by using fibroblasts and their interactions with the other cells of the thymus.
References:
  1. Clark, R.A. and T.S. Kupper, IL-15 and dermal fibroblasts induce proliferation of natural regulatory T cells isolated from human skin. Blood, 2007. 109(1): p. 194-202.
  2. Wood, G.W., Macrophages in the thymus. Surv Immunol Res, 1985. 4(3): p. 179-91.
  3. Akashi, K., et al., B lymphopoiesis in the thymus. J Immunol, 2000. 164(10): p. 5221-6.
  4. Proietto, A.I., et al., Dendritic cells in the thymus contribute to T-regulatory cell induction. Proc Natl Acad Sci U S A, 2008. 105(50): p. 19869-74.
  5. Wang, H., et al., Myeloid cells activate iNKT cells to produce IL-4 in the thymic medulla. Proc Natl Acad Sci U S A, 2019. 116(44): p. 22262-22268.
  6. Wang, W., et al., Thymic Function Associated With Cancer Development, Relapse, and Antitumor Immunity – A Mini-Review. Front Immunol, 2020. 11: p. 773.
Spleen. The spleen is one of the key secondary lymphoid organs responsible for the rapid response of the immune system to pathogens in the blood, and to maintain a long term adaptive response to such pathogens. The spleen also serves as the key organ for iron metabolism and erythrocyte homeostasis. The organ also functions as key storage site for platelets and leukocytes. A verity of cells have been identified in the spleen, including, endothelia cells, mesothelial cells, reticular cells, erythrocytes, granulocytes, mononuclear cells, hemopoietic cells, macrophages, dendritic cells, plasma cells,  CD4+ and CD8+ T cells, and migrating B cells. With age, the structure and function of the spleen changes, leading to decreased ability to respond positively to vaccination, increased susceptibility to viral and bacterial pathogen infections, and increased incidence of autoimmune disease1. Fibroblasts are no longer considered as mere structural components of organs but as dynamic participants in immune processes. Fibroblasts produce an environment that influences T regulatory cell migration, proliferation, and activity to ensure immunotolerance2. With an increase in lifespan, and a greater percentage of aged in the population, there is a need for improving and extending the productive life of the spleen through cell therapy using fibroblasts and their interactions with the other cells in the spleen.

References:

  1. Quandelacy, T.M., et al., Age- and sex-related risk factors for influenza-associated mortality in the United States between 1997-2007. Am J Epidemiol, 2014. 179(2): p. 156-67.
  2. Turner, V.M. and N.A. Mabbott, Influence of ageing on the microarchitecture of the spleen and lymph nodes. Biogerontology, 2017. 18(5): p. 723-738.

Skin (wound healing). Fibroblasts are no longer considered mere structural components of organs but as dynamic participants in multiple systems such as the immune and the complex interplay of multiple systems involved in wound healing.

Skin is the largest organ in the human body encompassing about 15% of the total body weight, and serves multiple complex functions such as protection from external physical, chemical, and microbial impacts, maintenance of temperature and electrolyte balance, serves as a biofactory for the synthesis and metabolism of structural proteins, lipids, glycans, and signaling molecules, as well as an integral component of the immune, nervous, and endocrine systems1. As such, injury to the skin and the repair process to the skin is a well-tuned process involving multiple systems and cell types. Wound heading follows an intricately orchestrated process of haemostasis, inflammation, proliferation, epithelialization, and remodeling confined to the injury location2. In addition, fibroblasts and fibroblast secreted materials are involved in every step of the process.

Wound treatment forms a significant burden to the healthcare system and destroys quality of life for the victims of nonhealing wounds. Difficult to heal wounds, chronic wounds are persistent, time-consuming, and costly to treat. In addition, injury to the skin due to diseases such as diabetes or cancer, cuts, abrasions, bedsores, or burns can have a lasting impact on the physical, emotional, and psychological wellbeing of a patient.   While some injuries caused to the skin can heal normally and quickly, certain underlying health aspects such as age, health status, and certain diseases can adversely impact the intricately orchestrated wound healing process, thereby requiring external intervention to heal properly. Since fibroblasts are an integral part of every step in the wound healing process and, externally applied fibroblasts, or fibroblast derived materials on wounds can initiate, maintain, and accelerate the wound healing process in diabetic ulcers, non-healing wounds, surgical incisions, traumatic injuries, abrasions, skin disorders,  cuts, and burns.

References:

  1. Chuong, C.M., et al., What is the ‘true’ function of skin? Exp Dermatol, 2002. 11(2): p. 159-87.
  2. Bainbridge, P., Wound healing and the role of fibroblasts. J Wound Care, 2013. 22(8): p. 407-8, 410-12.

Access peer-reviewed articles and get accurate, relevant news about FibroBiologics