A Closer Look At Tissue And Cell Regeneration In CLI
Given the severe complications associated with critical limb ischemia (CLI), this author offers a revealing look at the research on tissue regeneration and stem cell therapy, and potential therapeutic applications in the future.
Critical limb ischemia (CLI) is an end-stage disease that is provoked by progressive obstruction of the peripheral arteries. It is often associated with long segments of involvement at multiple sites with distal vessel disease. The ischemic insult results in rest pain, which progresses to skin breakdown and gangrene unless ischemia is reversed immediately.
Treatment includes risk factor modification, medical treatment for the vascular symptoms, prevention of systemic complications and revascularization measures. The goals of therapy include restoration of straight line, pulsatile blood flow to relieve ischemia, achieve wound healing, relieve rest pain and avoid major amputation.
However, despite aggressive treatment, many patients with CLI either die or eventually have to undergo a major amputation. Surgical or endovascular (angioplasty and stenting) revascularization approaches are usually not possible due to the diffuse involvement and poor distal vessel reformation. Furthermore, comorbid conditions may adversely affect the outcome of surgical procedures.
Despite the technical advances in interventional and surgical revascularization procedures, a substantial number of patients with peripheral arterial occlusive disease (PAOD) and CLI remain. When it comes to these patients, amputation may be the only option.
Assessing The Research On Tissue Regeneration
Tissue regeneration via the use of stem/progenitor cells has been recognized as a maintenance or recovery system for many organs in adults. The isolation of endothelial progenitor cells (EPCs) derived from the peripheral blood was one of the amazing discoveries for the recognition of “neovessel formation” in adults that occurs as physiological and pathological responses.
These findings that EPCs are home to sites of neovascularization and differentiate into endothelial cells in situ are consistent with the notion of “vasculogenesis.”
Vasculogenesis is a critical paradigm that has been well described for embryonic neovascularization and was proposed recently for adults in whom a reservoir of stem or progenitor cells contributes to vascular organogenesis. On the basis of the regenerative potency, these stem cells/ progenitor cells are expected to be a key factor in therapeutic applications for ischemic diseases.1
The induction of therapeutic angiogenesis by stem cell implantation could provide therapeutic benefits and may help in limb salvage in patients with CLI. One can achieve angiogenesis (collateral formation) either through growth factors or gene encoding for these proteins. Asahara, et al., and Prockop showed that marrow stromal cells secrete many angiogenic cytokines and also have characteristics of stem cells for mesenchymal tissues. 2,3
Several investigators have reported beneficial effects of injecting bone marrow derived stem cells for those with coronary artery disease. 4-13
Using animal models with hind limb ischemia, Iba, et al., injected peripheral blood mononuclear cells (MNCs) or polymorphonuclear leukocytes along with platelets into ischemic limbs via intramuscular injection. Follow-up imaging revealed significant collateral vessel formation. 13,14
Al-Khaldi, et al., investigated the effect of autologous marrow stromal cells on neovascularization and blood flow in rat models with CLI. They detected an increase in vascular density, collateralization and increased blood flow in the ischemic limb. 15 Healing of skin ulcers has occurred in animal models with diabetes following stem cell injection. 16