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How Human Cord Blood Stem Cells Can Inhibit Cancer Progression in Skin Disorder Patients

Review of “Cord Blood‐Derived Stem Cells Suppress Fibrosis and May Prevent Malignant Progression in Recessive Dystrophic Epidermolysis Bullosa” from STEM CELLS by Stuart P. Atkinson 

Mutations in the Col7a1 gene lead to the development of recessive dystrophic epidermolysis bullosa (RDEB), a severe skin fragility disorder associated with recurrent erosions in the skin and mucous membranes and an elevated risk of co-developing cutaneous squamous cell carcinoma (cSCC). Recent research from Yanling Liao and Mitchell S. Cairo (New York Medical College, Valhalla, New York, USA) established that human cord blood‐derived stem cells (USSCs) represented an exciting means to enhance wound healing and suppress mucocutaneous blistering in an RDEB mouse model [1, 2]. Now, the duo return with a new STEM CELLS study to study the roles of TGFβ signaling in RDEB [3], given the reported links to fibrosis and malignancy [4-6], and USSCs in the inhibition of RDEB-related cSCC development.

Fusion of the hands and feet by a thin membrane of skin (mitten deformity) occurs in most severe generalized RDEB patients [7], and initial analyses of newly born RDEB model mice (col7a1−/−) demonstrated the early activation of TGFβ signaling via phosphorylation of Smad2/3 within the interdigital folds of the paws. Increased TGFβ signaling also associated with an increase in collagen fibril deposition and the elevated dermal expression of both matrix metalloproteinase (MMP)-9 and ‐13 (linked to tumor invasion and malignant transformation), suggestive of a chronic wounding environment. Treatment of these mice with intradermal injections of USSCs provided for the short-term suppression of TGFβ signaling, MMP‐9/MMP‐13 expression, and proinflammatory cytokine expression and the upregulation of anti‐fibrotic factor (TGFβ3 and Decorin) expression.

Meanwhile, coculture assays of USSCs with RDEB patient‐derived fibroblasts, keratinocytes (both derived from non-lesional and non-inflamed skin), and cSCC cells uncovered the constitutively active STAT (but not TGFβ) signaling and elevated MMP‐9/MMP‐13 expression in patient derived‐keratinocytes and cSCCs, indicative of a proinvasive tumor microenvironment. Again, the addition of USSCs to the coculture via a transwell insert suppressed MMP‐9/MMP‐13 via a paracrine acting mechanism, suggesting that USSCs can modulate RDEB keratinocyte migration, malignant transformation into cSCC, and invasion, although, the authors observed no effects on STAT signaling. 

While these preliminary data suggest that USSCs can prevent fibrosis and modulate the malignant transformation of keratinocytes and the invasiveness of cSCC, the authors note that further studies are required. Additional patient‐derived biological samples will be required to validate the effects of USSCs on TGFβ and STAT signaling in the RDEB patients‐derived cells and, additionally, they also aim to assess the consequences of continuous administration of USSCs to RDEB model mice in the expectation that this strategy will induce long‐term suppression of TGFβ signaling, thus preventing the development of mitten deformity.

For more on how human cord blood stem cells may represent an effective means to inhibit cancer progression in RDEB patients, stay tuned to the Stem Cells Portal!

References

  1. Liao Y, Itoh M, Yang A, et al., Human Cord Blood-Derived Unrestricted Somatic Stem Cells Promote Wound Healing and have Therapeutic Potential for Patients with Recessive Dystrophic Epidermolysis Bullosa. Cell Transplantation 2014;23:303-317.
  2. Liao Y, Ivanova L, Zhu H, et al., Rescue of the Mucocutaneous Manifestations by Human Cord Blood Derived Nonhematopoietic Stem Cells in a Mouse Model of Recessive Dystrophic Epidermolysis Bullosa. STEM CELLS 2015;33:1807-1817.
  3. Liao Y, Ivanova L, Zhu H, et al., Cord Blood-Derived Stem Cells Suppress Fibrosis and May Prevent Malignant Progression in Recessive Dystrophic Epidermolysis Bullosa. STEM CELLS 2018;36:1839-1850.
  4. Knaup J, Gruber C, Krammer B, et al., TGFbeta-signaling in squamous cell carcinoma occurring in recessive dystrophic epidermolysis bullosa. Analytical Cellular Pathology (Amsterdam) 2011;34:339-53.
  5. Odorisio T, Di Salvio M, Orecchia A, et al., Monozygotic twins discordant for recessive dystrophic epidermolysis bullosa phenotype highlight the role of TGF-beta signalling in modifying disease severity. Human Molecular Genetics 2014;23:3907-22.
  6. Nystrom A, Thriene K, Mittapalli V, et al., Losartan ameliorates dystrophic epidermolysis bullosa and uncovers new disease mechanisms. EMBO Molecular Medicine 2015;7:1211-28.
  7. Fine J-D, Johnson LB, Weiner M, et al., Pseudosyndactyly and Musculoskeletal Contractures in Inherited Epidermolysis Bullosa: Experience of the National Epidermolysis Bullosa Registry, 1986–2002. Journal of Hand Surgery (European Volume) 2005;30:14-22.