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Paracrine Signaling from Umbilical Cord Blood CD34+ cells Promotes Diabetic Wound Healing

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Review of “Topical Application of Culture‐Expanded CD34+ Umbilical Cord Blood Cells from Frozen Units Accelerates Healing of Diabetic Skin Wounds in Mice” from STEM CELLS Translational Medicine by Stuart P. Atkinson

Patients with type 2 diabetes mellitus (T2DM) suffer from chronic and non-healing wounds due to diabetes-induced peripheral arterial occlusive disease. Cell-based therapies employed to enhance the regeneration of skin wounds include treatment with the CD34+ fraction of blood, which includes hematopoietic stem cells (HSCs), endothelial precursor cells (EPCs), and circulating angiogenic cells (CACs) [1].

Previous studies from the laboratory of Ian M. Rogers (Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada) recently discovered that paracrine signaling from umbilical cord blood (UCB) CD34+ cells reduced secondary injury and improved the mobility of injured mice in the absence of tissue engraftment [2]. In a new STEM CELLS Translational Medicine study, Whiteley et al. employed a similar non-matched mouse model of diabetic wound healing to assess the contribution of paracrine signaling from UCB CD34+ cells to the therapeutic effect [3].

The authors cultured frozen UCB CD34+ units in Stem Span base medium containing fibroblast growth factor‐4 (FGF‐4), stem cell factor, and Flt3‐ligand for eight days [4]. This approach maintained a high frequency of CD34+ cells and an 8- to 10‐fold expansion of the total cell population. Encouragingly, the topical application of in vitro cultured CD34+ cells to full thickness skin excision wounds in db/db mice, chosen because they exhibit diabetic symptoms throughout life, led to statistically significant faster wound closure compared to the vehicle‐control at days 3, 7, 10, and 14 post‐treatment, and the regeneration of full-thickness skin.

Overall, this study indicates that in vitro cultured CD34+ cell transplantation represents an exciting approach for diabetic wound healing in mice and underlines the vital importance of paracrine signaling rather than direct cell engraftment. The authors note that the in vitro expansion strategy employed may potentially permit the treatment of hundreds of small wounds from a single frozen UCB unit, further boosting clinical potential.

Will we soon see umbilical cord blood CD34+ cell therapy to treat diabetic skin wounds in human patients? Stay tuned to the Stem Cells Portal to find out!

References

  1. van der Strate BWA, Popa ER, Schipper M, et al., Circulating human CD34+ progenitor cells modulate neovascularization and inflammation in a nude mouse model. Journal of Molecular and Cellular Cardiology 2007;42:1086-1097.
  2. Chua SJ, Bielecki R, Yamanaka N, et al., The effect of umbilical cord blood cells on outcomes after experimental traumatic spinal cord injury. Spine (Phila Pa 1976) 2010;35:1520-6.
  3. Whiteley J, Chow T, Adissu H, et al., Topical Application of Culture-Expanded CD34+ Umbilical Cord Blood Cells from Frozen Units Accelerates Healing of Diabetic Skin Wounds in Mice. STEM CELLS Translational Medicine 2018;7:591-601.
  4. Rogers I, Yamanaka N, Bielecki R, et al., Identification and analysis of in vitro cultured CD45-positive cells capable of multi-lineage differentiation. Experimental Cell Research 2007;313:1839-1852.