Milestone: Fully Differentiated Cells Yield Clones

Great news from investigators at the University of Connecticut and the University of Pittsburgh, who were able to produce clones from granulocytes (a type of blood cell that does not itself divide) and to show that differentiated cells are more efficient than stem cells for somatic cell nuclear transfer. In other words, no stem cells needed:

This is the first demonstration that an animal can be derived directly from a fully differentiated cell, report lead researchers Xiangzhong (Jerry) Yang, Ph.D., of the University of Connecticut, and Tao Cheng, M.D., of the University of Pittsburgh, in the journal Nature Genetics. Moreover, they say results of their studies provide compelling evidence that Dolly the sheep and other mammals cloned by somatic cell nuclear transfer were most likely derived from fully differentiated cells, not adult stem cells, as most have argued in the nine years since Dolly was first created. Because stem cells have the ability to self-renew and differentiate into any specialized cell type, they have been heralded for their promise for treating a variety of diseases and conditions. Yet, even for cloning of an embryo to the blastocyst stage, from which embryonic stem cells can be generated, adult stem cells have yielded disappointing results, with success rates in the range of 1 to 5 percent.
Somatic cell nuclear transfer (SCNT), the scientific term for cloning, involves creating an embryo by using a nucleus that’s been removed from a somatic cell — any cell other than a reproductive cell — and transferring it into an unfertilized egg that has had its chromosomes removed. Because the resulting new embryo contains the entire genome of the donor somatic cell it is an identical copy. This cloned embryo is then implanted into a surrogate mother, and, if the process is successful, is carried to term…
In their studies, the researchers compared the efficiency for cloning mice using a fully differentiated blood cell called a granulocyte with its ancestor cells at different stages: hematopoietic stem cells, which are found in bone marrow and give rise to all red and white blood cells, and progenitor cells. Granulocytes are well characterized white blood cells unique for their segmented nuclei and the numerous granules in the cells’ cytoplasm.
Surprisingly, the granulocytes were the most efficient donor cells for nuclear transfer among the different lineage cells, with 35 to 39 percent becoming a blastocyst, an early embryo consisting of about 100 to 150 cells, compared to 11 percent for the progenitor cells and only 4 percent for the stem cells. Only the granulocytes were able to produce two live cloned pups, although both died within a few hours of birth. As a control, the researchers performed nuclear transfer using embryonic stem cells; 49 percent developed to the blastocyst stage and 18 cloned pups were born…
Since Dolly, animal cloning using adult cells has been accomplished in more than a dozen mammalian species, but the process is highly inefficient. Even if the reconstructed eggs survive to the blastocyst stage, only a handful, at most, of these result in live young when implanted into a female.
Many have attributed cloning’s limited success to a theory that clones must be derived from adult stem cells, which reside in a specific area of each tissue and remain quiescent until they are activated by the presence of disease or tissue injury. Yet, if this were true, Drs. Yang and Cheng point out, the results of their studies would have found the adult stem cells to be more efficient than the other, more differentiated cells.
“Of the 1,828 nuclear transfers we performed with stem cells, very few could develop to the blastocyst stage and not one clone was produced. With such odds, it’s hard to believe that Dolly and other cloned animals could have possibly been derived from adult stem cells. Much more likely is that these animals were derived from fully differentiated tissue cells,” Dr. Yang argues.

The press release…
More at Nature…