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Generation of kidney tissues from human mesenchymal stem cells
in whole-embryo culture system

(Yokoo T et al., Proc Natl Acad Sci USA 2005;102:3296-300)
Summarized by:  Nitixa Patel and Walter Alzate

LAY SUMMARY

Stem cells are pluripotent, specialized cells with the unique capacity to self-renew, and to produce various cell types. Contrary to most cells of the body, such as heart cells or skin cells, which are committed to perform specific functions, a stem cell is uncommitted and remains so until it receives a signal to develop into mature cells. There are two major categories of stem cells: embryonic stem cells and adult stem cells. Adult stem cells are located in adult tissues, such as bone marrow, muscle and brain. The primary role of adult stem cells is to maintain and repair the tissue in which they reside. Repairs are sometimes needed due to normal wear and tear caused by injury and insults.

Until recently, it had been thought that a stem cell from a specific tissue could not give rise to cells of a different organ. However, a number of experiments over the last decade have challenged this premise, giving rise to two terms: plasticity and transdifferentiation. Examples of plasticity are the changes of bone marrow stem cells into neurons and liver cells.
Researchers in Japan have found evidence that adult bone marrow stem cells are capable of forming kidney cells. The researchers first identified and extracted a type of stem cell called mesenchymal stem cells from adult bone marrow of healthy humans (hMSCs). Subsequently, two types of gene were inserted into the chromosomes of these cells: a gene (GDNF) that expresses a substance that activates the kidney gene program; and another that distinguishes the hMSCs from the host cells (Lac Z gene). As control, the authors used non-stem cells called fibroblast.

Once they researchers had completed preparing the hMSCs, they removed embryos from rats and then maintain them outside of the uterus by a technique known as whole-embryo culture. hMSCs and control cells were injected into the embryo  at the site where the kidney develops. After 48 hours, the embryos were dissected and the tissues that give rise to kidney were removed and supported artificially in an environment where the tissue could undergo further development (referred as in vitro culture).

By day 6, the tissues were examined and were found to show the following:

• hMSCs were present in different layers of the mouse kidney while this was not observed when the non-stem cells were injected.
• The hMSC changed into cells that behave as kidney cells.
• The hMSCs were able to repair kidney malfunction.

Conclusion: It was concluded that adult hMSCs could be reprogrammed to generate other cell fates and to form organ structures. The type of organ that the hMSCs form depends on the region of the embryo where the cells find themselves.

Thoughts: Evidently this technology could render organ transplantation obsolete since adult stem cells might be able to generate whole organs. If the person’s own stem cells are used to generate an organ, e.g., a kidney, then this would eliminate searching for a donor that matches, and also prevent the organ from rejection.

SCIENTIFIC

Organ regeneration is gaining much attention as a new therapeutic strategy.  To be able to establish autologous organs from adult stem cells, the premise is that the organ would be developed in vitro and then syngrafted back into the donor. In this study the authors established an in vitro system to build organ structures from autologous adult human mesenchymal stem cells (hMSCs), cultivated in rodent embryos. hMSCs were injected into the site of kidney organogenesis. The implanted hMSCs were discriminated from the murine host cells by the expression of LacZ gene (b-galactosidase) and DiI. In addition successful implantation was determined by in situ hybridization for human genomic AluI/II.

The authors showed the integration of hMSCs and the generation of renal structures, based on LacZ expression. The hMSCs dispersed throughout the metanephric rudiment of the kidney. The newly formed kidney cells were morphologically identical to the host glomerular epithelial cells, tubular epithelial cells, and interstitial cells. The hMSC-derived nephrons were tested for functionality; the stem cells were transplanted in α-Gal A-null Fabry mouse. If the hMSC-derived nephons could repair the defect in the Fabry mouse, then there should be resolution of abnormal accumulation of glycosphingolipids to prevent renal failure after birth. Indeed, the authors showed noticeable resolution of the defect in the Fabry mice. This confirmed that the hMSC-derived nephrons were biologically functional.

This study showed that allowing hMSCs to grow in specific organ locations in whole-embryo culture commits them to the same morphological fate as cells endogenous to that organ.  An advantage to using hMSCs is that they can transdifferentiate into cells from ectodermal or endodermal cells.  This study has illustrated the possibility of generating organs from autologous adult MSCs.