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Autologous Transplantation of Granulocyte Colony–Stimulating Factor–Mobilized Peripheral Blood Mononuclear Cells Improves Critical Limb Ischemia in Diabetes

Response to Fadini and Avogaro

¹ State Key Laboratory of Experimental Hematology, National Research Center for Stem Cell Engineering and Technology, Institute of Hematology, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
² National Engineering Research Center of Cell Products, AmCellGene, Teda, Tianjin, China

Address correspondence to Zhong Chao Han, Institute of Hematology, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Rd., Tianjin 300020, China. E-mail: tihzchan{at}public.tpt.tj.cn

Recently, our pilot study provided evidence that autologous transplantation of granulocyte colony–stimulating factor–mobilized peripheral blood mononuclear cells (PBMNCs) may represent a simple, safe, effective, and novel therapeutic approach for diabetic critical limb ischemia (CLI) (1). In our study, we chose diabetic patients with proven CLI, but without hypercoagulable states and/or severe coronary, cerebral, and renal vascular disease. As pointed out by Fadini and Avogaro (2), poor blood vessel growth in ischemic hearts and limbs and increased angiogenesis in retinal complications are paradoxical vascular complications in diabetic patients. This so-called "diabetic paradox" has been attributed to the differential regulation of angiogenic factors in the retina versus the systemic circulation (3). Thus, we may have to choose a compromised approach to balance these two divergent complications. For patients with mild or absent retinal complications but very severe limb ischemia that manifests ulceration, gangrene, or nonhealing wounds, we may give priority to improving CLI. We agree that we must be cognizant of a treatment approach that focuses on improving CLI, as well as remain aware of the potential risk for worsening diabetic retinopathy. In addition, we must monitor undesirable retinal vascular changes.

Dysfunctional endothelial progenitor cells (EPCs) from diabetes (4) may attenuate the effectiveness of our approach for CLI. However, we have observed that mobilized PBMNCs yielded more EPCs from diabetic individuals than nonmobilized ones, partially compensating for the fewer number of EPCs in diabetes. In addition, our results revealed that the mechanism in vivo is not limited to EPCs. Proangiogenic factors secreted by mononuclear cells played an equally important role in vivo (S. Li, B.Z., Z.C.H., unpublished data). Clinically, allogenic transplantation of normal mobilized PBMNCs may be more effective, but such transplanted cells may encounter rejection. Therefore, autologous transplantation of mobilized PBMNCs is still a good, albeit compromised and imperfect, approach.

As for decreased plasma glucose, we proposed that mobilization resulted in more circulating EPCs that could be recruited to the pancreas and that EPC-mediated neovascularization of the pancreas could in principle facilitate the recovery of non–terminally injured cells (5). The precise mechanism of decreased plasma glucose after mobilization awaits further investigation, for which a much higher number of patients will need to be involved.

Acknowledgments

This work was supported by grants from the Ministry of Science & Technology of China 863 project (2002AA223354) and 973 project (001CB5101).

References

1. Huang P, Li S, Han M, Xiao Z, Yang R, Han ZC: Autologous transplantation of granulocyte colony–stimulating factor–mobilized peripheral blood mononuclear cells improves critical limb ischemia in diabetes. Diabetes Care 28:2155–2160, 2005[Abstract/Free Full Text]
   
2. Fadini GP, Avogaro A: Autologous transplantation of granulocyte colony–stimulating factor–mobilized peripheral blood mononuclear cells improves critical limb ischemia in diabetes (Letter). Diabetes Care 29:478–479, 2006[Free Full Text]
   
3. Duh E, Aiello LP: Vascular endothelial growth factor and diabetes: the agonist versus antagonist paradox. Diabetes 48:1899–1906, 1999[Abstract]
   
4. Loomans CJ, de Koning EJ, Staal FJ, Rookmaaker MB, Verseyden C, de Boer HC, Verhaar MC, Braam B, Rabelink TJ, Zonneveld AJ: Endothelial progenitor cell dysfunction: a novel concept in the pathogenesis of vascular complications of type 1 diabetes. Diabetes 53:195–199, 2004[Abstract/Free Full Text]
   
5. Mathews V, Hanson PT, Ford E, Fujita J, Polonsky KS, Graubert TA: Recruitment of bone marrow-derived endothelial cells to sites of pancreatic ß-cell injury. Diabetes 53:91–98, 2004[Abstract/Free Full Text]
   

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This Article Extract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Zhou, B. Articles by Han, Z. C. Search for Related Content PubMed Articles by Zhou, B. Articles by Han, Z. C. Social Bookmarking                What's this?