**5. Conclusion**

cells. Moreover, inflammation-related cytokine growth factor mRNAs for interleukins (IL)-6, -11, -1A, -1B, and -18 are upregulated along with angiogenic-associated growth factor mRNAs for epiregulin (EREG), chemokine (C-X-C motif) ligand 1 (CXCL1), teratocarcinoma-derived growth factor (TDGF1), fibroblast growth factor 5 (FGF5), C-fos induced growth factor (FIGF), and vascular endothelial growth factor A (VEGFA) that have the potential to improve microcir‐ culation within the injuredregions.In additionto the above growthfactors, expressionoftrefoil factor 1 (TFF1), colony stimulating factor 3 (CSF3), hepatocyte growth factor (HGF), and bone morphogenetic protein 1 (BMP1) mRNAs is also elevated. The roles of these growth factors are

Collectively, these results show that cells of the urinary bladder respond to freeze injury by enhanced transcription of mRNAs specifically associated with differentiation of smooth muscle cells and wound healing. If translated, expression of these genes can promote growth and development of a suitable physical and biochemical environment. Under these circum‐ stances, the microenvironment within the freeze-injured urinary bladders would promote

It is likely that recovery within the freeze-injured urinary bladders requires participation of the undamaged tissue adjacent to the injured site [1, 21]. In general, the success of implanted undifferentiated cells depends upon the recovery of host cells to provide an appropriate microenvironment at the location of the injury or disease site. These host cells are necessary to support the production of growth factors by the implanted bone marrow-derived cells [52-54]. The absence of a supportive microenvironment in the surrounding host tissues, as might occur in cases of irreversible or chronic diseases and/or injuries of the urinary bladder due to spinal injury or radiation therapy, might prevent or limit the recovery processes

Tissue engineering consists of three components: (1) undifferentiated cells having the potential to differentiate into specific cell types, (2) scaffolding to support construction of tissue structures, and (3) growth factors to promote differentiation of various and specific cell types. The bone marrow-derived cells are an excellent source of multipotent undifferentiated cells that can develop into smooth muscle cells [1, 14, 55, 56]. The tissue pores that are present three days after freeze-injury operation are likely to provide scaffolding and spaces suitable for colonization by the implanted bone marrow-derived cells. This would optimize the chance for a high rate of cell survival and differentiation [21]. Though we have not actually measured the secretion of growth factors by the surviving cells, at least 19 different growth factor mRNAs are increased three days after the freeze-injury operation. These mRNAs includes growth factor mRNAs for SPP1, INHBA, GDNF, and TGFB1 [21]. If they are translated, they would be able to support the differentiation of the implanted bone marrow-derived cells into smooth muscle cells. Finally, the maintenance of a minimal microcirculation within the injured regions probably supports growth and development of the implanted bone marrow-derived cells [21].

unclear, but it is likely that they participate in wound healing.

**4.4. Uninjured regions in the freeze–injured urinary bladders**

associated with the implanted cells.

422 Regenerative Medicine and Tissue Engineering

**4.5. Tissue engineering**

organization of the developing cells into physiologically functional tissues.

This chapter shows that bone marrow-derived cells have the potential to be an important cell source for regeneration of lower urinary tracts. The implantation of bone marrow-derived cells can produce functional smooth muscle layers in irreversibly damaged urinary bladders associated with the loss of smooth muscle layers due to injury or disease. Also, the cell implantation can recover functional urethral sphincters that prohibit the inadvertent release of urine. We suggest that to develop the full clinical potential of regenerative medicine, we need a further understanding of the requirements for undifferentiated cell proliferation and targeted differentiation. Moreover, based on tissue engineering principles, knowledge of each unique microenvironment within recipient tissues is necessary.
