New Sources of Stem Cells

Despite initial enthusiasm to use adult bone marrow stem cells for organ regeneration, evidence suggests that adult bone marrow contains limited numbers of organ-specific stem cells. Adult bone marrow has sufficient numbers of stem cells to reconstitute hematopoietic cells but diminishing numbers of stem cells to contribute to vascular regeneration. Other sources of organ-specific stem cells to generate vascularized pancreatic islet cells, myogenic cells, or neuronal cells may be necessary to treat diabetes, myocardial infarction, or stroke. Human embryonic stem cells provide a rich source of stem cells for therapeutic purposes. In collaboration with Zev Rosenwaks (Cornell University Weill Medical College), we have generated and cultured two validated human embryonic stem cell lines-Weill-Cornell-1 (WC-1) and WC-2. We are establishing protocols to generate functional blood vessels from human embryonic stem cells.

In a remarkable breakthrough, we have identified another source of stem cells that may be used therapeutically for organ regeneration. We have isolated large numbers of mouse spermatogonial stem cells and differentiated them into adult multipotent cells, with the potential to differentiate into endothelial cells, myogenic cells, and neuronal cells. We are examining the potential of spermatogonial stem cells derived from humans to differentiate into autologous human adult multipotent cells.

Scalability. If the goal of stem cell therapeutics is to generate vascularized human tissues, substantial numbers of stem cells will be necessary. Therefore, stem cells with the capacity to undergo expansion are ideal sources of cells for therapeutic organ revascularization. Current hurdles in expanding human adult stem cells limit the amount of tissue that may be necessary to regenerate a damaged organ or target tumors. Therefore, human embryonic stem cells, which can be expanded in large numbers, are an indispensable source of transplantable human tissue. One advantage of spermatogonial-derived cells is that they allow for generation of large numbers of autologous spermatogonial stem cells, circumventing the immune rejection or graft-versus-host responses.

Circumventing the need for a genetic match. Currently, bone marrow transplantation for hematological disorders has one major shortcoming: in many cases the proper genetic match is not available. Human embryonic stem cells, especially spermatogonial stem cells, allow for generating autologous stem cells for therapeutic organ regeneration. Development of human embryonic stem cell or spermatogonial stem cell technology will have a tremendous impact on the treatment of a wide variety of patients.

Despite availability of sophisticated bone marrow registry and blood banks, there are many patients with leukemias, lymphomas, or solid tumors who succumb to their disease because a genetically suitable match is not available. Many patients also receive marrow that is not a perfect genetic match, resulting in disabling graft-versus-host disease.

Derivation of human embryonic, spermatogonial, and oogonial stem cells could provide an unlimited source of genetically matched autologous stem cells for organ regeneration and tumor targeting, as well as treatment of genetic disorders, including diabetes, heart disease, stroke, and vascular diseases. We are also investigating tumor vessel targeting, which could be applied to common cancers, including lung, breast, esophageal, and colon cancers.

Our lab is studying the potential of stem cells for therapeutic organ vascularization in three models:

1. Lung regeneration: Removal of the left lung of the mouse results in the regeneration of the remaining right lung. We have shown that marrow-derived progenitors contribute to the revascularization of the remaining right lung.

2. Liver regeneration: Partial hepatectomy promotes recruitment of liver oval stem cells expressing VEGF-R1 (vascular endothelial growth factor receptor-1) to contribute to neo-angiogenesis and liver regeneration. This model allows us to examine the role of hemangiogenic progenitors and preconditioning in organ regeneration.

3. Cardiac and ischemic limb preconditioning: Acute ischemia induced by the ligation of the left anterior descending coronary artery or femoral artery will allow us to examine the role of preconditioning of the recipient neo-angiogenic niche with PDGF (platelet-derived growth factor) and/or BDNF (brain-derived neurotrophic factor) in incorporation of the hemangiogenic progenitor cells into ischemic tissues.