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. Fibroblasts do not require costly additives required for stem cells, which reduces 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

Degenerative Disc Disease (DDD) Fibroblasts are a potential substitute for Mesenchymal stem cells (MSCs) in treating DDD. Read more

5

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.

Fibroblasts are a practical and economical alternative to stem cells for cell therapy

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 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 variety 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.

Degenerative Disc Disease (DDD). Current regenerative approaches to degenerative disc disease (DDD) are limited by lack of efficacy, limited sources of raw materials, and cost of production. Fibroblasts are available in ample numbers and are inexpensive to expand in vitro. CybroCell™ is a fibroblast-based universal donor cellular product, which has demonstrated safety and efficacy in preclinical models of DDD. The current study aims to assess safety and efficacy.

It is estimated that approximately 632 million people worldwide are affected by lower back pain, with annual costs in the United States estimated to exceed $100 billion1-3. Degenerative disc disease (DDD), also known as intervertebral disc (IVD) degeneration, is a condition associated with the progressive and irreversible deterioration of one or more of the discs in the spine. Although not all patients with radiological evidence of DDD have lower back pain, DDD is considered one of the major causes of chronic lower back pain4-6.

It is recognized that there are multiple possible and complicated causes of DDD, including genetic, nutritional, and mechanical influences7-9. The processes associated with the degeneration of the disc include a progressive decline in nucleus pulposus (NP) hydration due to the loss of extracellular matrix (ECM) molecules such as aggrecan and collagen10, 11, which is associated in part with reduced oxygenation and increased acidification12. In addition, inflammatory processes such as increased TNF-alpha13-16, macrophage activation17, and NF-kappa B translocation18-22, result in the activation of matrix metalloproteases, which further cause degradation of ECM. Furthermore, these processes result in the apoptosis of cells in the NP, which further results in reduction of ECM synthesis23-25.

This decreased disc hydration results in a loss of mechanical tension in the collagen fibers of the annulus fibrosus and results in abnormal spinal axial loading forces and segmental instability26. Eventually, disc degeneration progresses to cause abnormalities of other components of the disc space, like the endplate and facet joint, which can develop into serious conditions, such as disc herniation, spondylolisthesis, spinal canal stenosis, or facet joint syndrome27-29.

Recent studies have focused on using adult stem cells for disorders such as degenerative disc disease. Mesenchymal stem cells (MSCs) are non-hematopoietic, multipotent progenitor cells that can be isolated from various human adult tissues30. The potential to form cells of multi-lineages has indicated the potential of these cells in cases of degenerative disc disease31. In recent years, MSCs have been shown to possess a broad range of regenerative capabilities, modulating disease progression by repairing lesions closely associated with degenerative disc disease32, 33.

Although MSCs possess various regenerative properties, issues with isolation, expansion, and culturing cost limit their widespread utilization. One potential substitute for MSCs are fibroblasts, which can be readily acquired in large numbers, are relatively easy to expand in vitro, and are economical to produce. Studies show fibroblasts possess a differentiation potential similar to MSC. In one report, mechanical stimulation was applied to dermal fibroblast cells encapsulated in alginate beads using a custom-built bioreactor system for either a 1- or 3-week period at a frequency of 1 Hz for four hours/day under hypoxic conditions. Chondrogenic differentiation of the fibroblasts was observed, as indicated by elevated aggrecan gene expression and an increased collagen production rate34. In vivo ability of fibroblasts to differentiate into chondrogenic cells was demonstrated in a subsequent study. In a recent paper, researchers induced disc degeneration in New Zealand white rabbits by annular puncture and, after four weeks, intradiscally implanted human dermal fibroblasts or saline. Eight weeks after cellular implantation, there was a significant disc height increase in the treated discs compared to control fibroblasts, as well as reduced expression of inflammatory markers, a higher ratio of collagen type II over collagen type I gene expression, and more intense immunohistochemical staining for both collagen types I and II35. An independent group conducted a subsequent study where eight rabbits underwent disc puncture to induce disc degeneration. One month later, cultured fibroblasts, taken from the skin, were injected into the disc. The viability and the potential of the injected cells for reproduction were studied histologically and radiologically. Cellular formations and organizations indicative of histological recovery were observed in the discs to which fibroblasts were transplanted. The histological findings of the discs not transplanted with fibroblasts showed no histological recovery. Radiologically, no finding of improvement was found in both group. However, the fibroblasts injected into the degenerated discs were viable36.

In addition to differentiation into chondrocytic tissues, other studies have shown that fibroblasts can differentiate into other types of cells. In one study, cultured human adult bronchial fibroblast-like cells (Br) were assessed in comparison with mesenchymal cell progenitors isolated from fetal lung (ICIG7) and adult bone marrow (BM212) tissues. Surface immunophenotyping by flow cytometry revealed a similar expression pattern of antigens characteristic of marrow-derived MSCs, including CD34 (-), CD45 (-), CD90/Thy-1 (+), CD73/SH3, SH4 (+), CD105/SH2 (+) and CD166/ALCAM (+) in Br, ICIG7 and BM212 cells. One exception was the STRO-1 antigen, which was only weakly expressed in Br cells. Analysis of cytoskeleton and matrix composition by immunostaining showed that lung and marrow-derived cells homogeneously expressed vimentin and nestin proteins in intermediate filaments. At the same time, they were all devoid of epithelial cytokeratins.

Additionally, alpha-smooth muscle actin was also present in microfilaments of a low number of cells. All cell types predominantly produced collagen and fibronectin extracellular matrix as evidenced by staining with the monoclonal antibodies for collagen prolyl 4-hydroxylase and fibronectin isoforms containing the extradomain (ED)-A together with ED-B in ICIG7 cells. Br cells similar to fetal lung and marrow fibroblasts could differentiate along the three adipogenic, osteogenic and chondrogenic mesenchymal pathways when cultured under appropriate inducible conditions. Altogether, this data indicates that MSCs are present in human adult lungs. They may be actively involved in lung tissue repair under physiological and pathological circumstances37.

Further support for multi-lineage differentiation of fibroblasts used cells isolated from juvenile foreskins—these cells were shown to share a mesenchymal stem cell phenotype and multi-lineage differentiation potential. Specifically, the investigators demonstrated similar expression patterns for CD14(-), CD29(+), CD31(-), CD34(-), CD44(+), CD45(-), CD71(+), CD73/SH3-SH4(+), CD90/Thy-1(+), CD105/SH2(+), CD133(-) and CD166/ALCAM(+) in well-established adipose tissue-derived stem cells and foreskin fibroblastic cells by flow cytometry.

Immunostainings showed fibroblast cells expressed vimentin, fibronectin, and collagen; they were less positive for alpha-smooth muscle actin and nestin, while they were negative for epithelial cytokeratins. Both cell types could differentiate along the adipogenic and osteogenic lineages when cultured under appropriate inducible conditions. Additionally, fibroblasts demonstrated a higher proliferation potential than mesenchymal stem cells. These findings are significant because skin or adipose tissues are easily accessible for cell transplantations in regenerative medicine38. Verification of multi-lineage differentiation of foreskin fibroblasts was provided by a study in which foreskin fibroblasts were demonstrated to possess shorter doubling time than MSC, as well as the ability to multiply more than 50 doublings without undergoing senescence. The cells were positive for the MSC markers CD90, CD105, CD166, CD73, SH3, and SH4 and could be induced to differentiate into osteocytes, adipocytes, neural cells, smooth muscle cells, Schwann-like cells, and hepatocyte-like cells39.

References:

  1. Katz JN. Lumbar disc disorders and low-back pain: socioeconomic factors and consequences. J Bone Joint Surg Am 2006;88 Suppl 2:21-24.
  2. Vos T, Flaxman AD, Naghavi M, Lozano R, Michaud C, Ezzati M, Shibuya K, et al. Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012;380:2163-2196.
  3. Andersson GB. Epidemiological features of chronic low-back pain. Lancet 1999;354:581-585.
  4. Smith LJ, Nerurkar NL, Choi KS, Harfe BD, Elliott DM. Degeneration and regeneration of the intervertebral disc: lessons from development. Dis Model Mech 2011;4:31-41.
  5. Chou R. In the clinic. Low back pain. Ann Intern Med 2014;160:ITC6-1.
  6. Raj PP. Intervertebral disc: anatomy-physiology-pathophysiology-treatment. Pain Pract 2008;8:18-44.
  7. Bibby SR, Urban JP. Effect of nutrient deprivation on the viability of intervertebral disc cells. Eur Spine J 2004;13:695-701.
  8. Bartels EM, Fairbank JC, Winlove CP, Urban JP. Oxygen and lactate concentrations measured in vivo in the intervertebral discs of patients with scoliosis and back pain. Spine (Phila Pa 1976) 1998;23:1-7; discussion 8.
  9. Grunhagen T, Wilde G, Soukane DM, Shirazi-Adl SA, Urban JP. Nutrient supply and intervertebral disc metabolism. J Bone Joint Surg Am 2006;88 Suppl 2:30-35.
  10. Buckwalter JA. Aging and degeneration of the human intervertebral disc. Spine (Phila Pa 1976) 1995;20:1307-1314.
  11. Costi JJ, Stokes IA, Gardner-Morse MG, Iatridis JC. Frequency-dependent behavior of the intervertebral disc in response to each of six degree of freedom dynamic loading: solid phase and fluid phase contributions. Spine (Phila Pa 1976) 2008;33:1731-1738.
  12. Fu J, Yu W, Jiang D. Acidic pH promotes nucleus pulposus cell senescence through activating the p38 MAPK pathway. Biosci Rep 2018;38.
  13. Liu H, Kang H, Song C, Lei Z, Li L, Guo J, Xu Y, et al. Urolithin A Inhibits the Catabolic Effect of TNFalpha on Nucleus Pulposus Cell and Alleviates Intervertebral Disc Degeneration in vivo. Front Pharmacol 2018;9:1043.
  14. Abdollahzade S, Hanaei S, Sadr M, Mirbolouk MH, Fattahi E, Rezaei N, Khoshnevisan A. Significant association of TNF-alpha, but not other pro-inflammatory cytokines, single nucleotide polymorphisms with intervertebral disc degeneration in Iranian population. Clin Neurol Neurosurg 2018;173:77-83.
  15. Evashwick-Rogler TW, Lai A, Watanabe H, Salandra JM, Winkelstein BA, Cho SK, Hecht AC, et al. Inhibiting tumor necrosis factor-alpha at time of induced intervertebral disc injury limits long-term pain and degeneration in a rat model. JOR Spine 2018;1.
  16. Wang H, He P, Pan H, Long J, Wang J, Li Z, Liu H, et al. Circular RNA circ-4099 is induced by TNF-alpha and regulates ECM synthesis by blocking miR-616-5p inhibition of Sox9 in intervertebral disc degeneration. Exp Mol Med 2018;50:27.
  17. Hamamoto H, Miyamoto H, Doita M, Takada T, Nishida K, Kurosaka M. Capability of nondegenerated and degenerated discs in producing inflammatory agents with or without macrophage interaction. Spine (Phila Pa 1976) 2012;37:161-167.
  18. Liang H, Yang X, Liu C, Sun Z, Wang X. Effect of NF-kB signaling pathway on the expression of MIF, TNF-alpha, IL-6 in the regulation of intervertebral disc degeneration. J Musculoskelet Neuronal Interact 2018;18:551-556.
  19. Sun J, Hong J, Sun S, Wang X, Peng Y, Zhou J, Huang Y, et al. Transcription factor 7-like 2 controls matrix degradation through nuclear factor kappaB signaling and is repressed by microRNA-155 in nucleus pulposus cells. Biomed Pharmacother 2018;108:646-655.
  20. Luo L, Gao Y, Yang C, Shao Z, Wu X, Li S, Xiong L, et al. Halofuginone attenuates intervertebral discs degeneration by suppressing collagen I production and inactivating TGFbeta and NF-small ka, CyrillicB pathway. Biomed Pharmacother 2018;101:745-753.
  21. Yang H, Tian W, Wang S, Liu X, Wang Z, Hou L, Ge J, et al. TSG-6 secreted by bone marrow mesenchymal stem cells attenuates intervertebral disc degeneration by inhibiting the TLR2/NF-kappaB signaling pathway. Lab Invest 2018;98:755-772.
  22. Wu X, Liu Y, Guo X, Zhou W, Wang L, Shi J, Tao Y, et al. Prolactin inhibits the progression of intervertebral disc degeneration through inactivation of the NF-kappaB pathway in rats. Cell Death Dis 2018;9:98.
  23. Zhang J, Wang X, Liu H, Li Z, Chen F, Wang H, Zheng Z, et al. TNF-alpha enhances apoptosis by promoting chop expression in nucleus pulposus cells: role of the MAPK and NF-kappaB pathways. J Orthop Res 2018.
  24. Wang W, Deng G, Qiu Y, Huang X, Xi Y, Yu J, Yang X, et al. Transplantation of allogenic nucleus pulposus cells attenuates intervertebral disc degeneration by inhibiting apoptosis and increasing migration. Int J Mol Med 2018;41:2553-2564.
  25. Merceron C, Mangiavini L, Robling A, Wilson TL, Giaccia AJ, Shapiro IM, Schipani E, et al. Loss of HIF-1alpha in the notochord results in cell death and complete disappearance of the nucleus pulposus. PLoS One 2014;9:e110768.
  26. Pennicooke B, Moriguchi Y, Hussain I, Bonssar L, Hartl R. Biological Treatment Approaches for Degenerative Disc Disease: A Review of Clinical Trials and Future Directions. Cureus 2016;8:e892.
  27. Antoniou J, Steffen T, Nelson F, Winterbottom N, Hollander AP, Poole RA, Aebi M, et al. The human lumbar intervertebral disc: evidence for changes in the biosynthesis and denaturation of the extracellular matrix with growth, maturation, ageing, and degeneration. J Clin Invest 1996;98:996-1003.
  28. Martin MD, Boxell CM, Malone DG. Pathophysiology of lumbar disc degeneration: a review of the literature. Neurosurg Focus 2002;13:E1.
  29. Buser Z, Chung AS, Abedi A, Wang JC. The future of disc surgery and regeneration. Int Orthop 2018.
  30. Basso M, Cavagnaro L, Zanirato A, Divano S, Formica C, Formica M, Felli L. What is the clinical evidence on regenerative medicine in intervertebral disc degeneration? Musculoskelet Surg 2017;101:93-104.
  31. Wei A, Shen B, Williams L, Diwan A. Mesenchymal stem cells: potential application in intervertebral disc regeneration. Transl Pediatr 2014;3:71-90.
  32. Kumar H, Ha DH, Lee EJ, Park JH, Shim JH, Ahn TK, Kim KT, et al. Safety and tolerability of intradiscal implantation of combined autologous adipose-derived mesenchymal stem cells and hyaluronic acid in patients with chronic discogenic low back pain: 1-year follow-up of a phase I study. Stem Cell Res Ther 2017;8:262.
  33. Oehme D, Goldschlager T, Ghosh P, Rosenfeld JV, Jenkin G. Cell-Based Therapies Used to Treat Lumbar Degenerative Disc Disease: A Systematic Review of Animal Studies and Human Clinical Trials. Stem Cells Int 2015;2015:946031.
  34. Singh M, Pierpoint M, Mikos AG, Kasper FK. Chondrogenic differentiation of neonatal human dermal fibroblasts encapsulated in alginate beads with hydrostatic compression under hypoxic conditions in the presence of bone morphogenetic protein-2. J Biomed Mater Res A 2011;98:412-424.
  35. Chee A, Shi P, Cha T, Kao TH, Yang SH, Zhu J, Chen D, et al. Cell Therapy with Human Dermal Fibroblasts Enhances Intervertebral Disk Repair and Decreases Inflammation in the Rabbit Model. Global Spine J 2016;6:771-779.
  36. Ural IH, Alptekin K, Ketenci A, Solakoglu S, Alpak H, Ozyalcin S. Fibroblast Transplantation Results to the Degenerated Rabbit Lumbar Intervertebral Discs. Open Orthop J 2017;11:404-416.
  37. Sabatini F, Petecchia L, Tavian M, Jodon de Villeroche V, Rossi GA, Brouty-Boye D. Human bronchial fibroblasts exhibit a mesenchymal stem cell phenotype and multi-lineage differentiating potentialities. Lab Invest 2005;85:962-971.
  38. Lorenz K, Sicker M, Schmelzer E, Rupf T, Salvetter J, Schulz-Siegmund M, Bader A. Multilineage differentiation potential of human dermal skin-derived fibroblasts. Exp Dermatol 2008;17:925-932.
  39. Huang HI, Chen SK, Ling QD, Chien CC, Liu HT, Chan SH. Multi-lineage differentiation potential of fibroblast-like stromal cells derived from human skin. Tissue Eng Part A 2010;16:1491-1501.

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.

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