Scientists Convert Human Skin Cells Directly Into Brain Cells

Using a finely tuned cocktail of small molecules, researchers from Washington University in St. Louishave successfully converted adult skin cells into the major type of brain cell affected in the fatal neurodegenerative disorder Huntington’s disease. For the first time, this was achieved without the need to go through a stem cell intermediate, avoiding the production of other types of cell. Importantly, when the researchers transplanted these cells into the brains of mice, they survived and showed similar properties to native cells. While it is still in the early days, these preliminary results could suggest that in the future, this technique may be developed further to help patients with Huntington’s. The work has been published in Neuron.

Huntington’s disease is an inherited brain disorder that causes the progressive degeneration of nerve cells, or neurons. This disease predominantly affects a type of cell called medium spiny neurons (MSNs), which are crucial for movement control. As they are gradually lost in the brain, the patient experiences involuntary muscle movements and cognitive decline. While there is currently no cure, a future possible treatment avenue could involve replacing the lost cells in the brain. But first, researchers need to work out a way to not only produce these cells, but also to ensure they are not rejected by the patient, which is what the Washington University scientists are working towards.

Previous work by this team found that it is possible to turn skin cells into different types of brain cell by exposing them to two small molecules of RNA, a similar molecule to DNA. These specific "microRNAs” unravel target stretches of DNA, or genes, which are responsible for the identity of the cell. In doing so, proteins called transcription factors can access the DNA sequences, which result in the expression of genes which govern the development of neurons. Armed with this knowledge, the researchers added to these cells the same transcription factors present in brain regions containing MSNs. This combination of ingredients was found to result in the direct conversion of skin cells into this specific type of neuron.

“We think that the microRNAs are really doing the heavy lifting,” co-first author Matheus Victor said in a news-release. “They are priming the skin cells to become neurons. The transcription factors we add then guide the skin cells to become a specific subtype, in this case medium spiny neurons. We think we could produce different types of neurons by switching out different transcription factors.”

When the researchers analyzed these reprogrammed cells, they were found to show similar gene expression profiles to human MSNs. Furthermore, after they were transplanted into the brains of mice, they survived for over 6 months, exhibited similar properties to the native MSNs and even connected to distant neuronal targets in the brain.

The researchers are now taking this work one step further by using the same technique on skin cells taken from Huntington’s patients. To investigate whether these cells can alleviate some of the symptoms associated with the disease in animals, the researchers plan to transplant these cells into mouse models of Huntington’s.

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Invasive Micropapillary Carcinoma of the Breast


  • Breast carcinoma with a prominent (pseudo) micropapillary pattern

Diagnostic Criteria

  • Numerous small pseudo-papillary clusters of cells
    • No fibrovascular cores
    • Frequent central lumen formation in clusters
    • Peripherally located nuclei frequently bulge out with knobby appearance, "the hedgehog" tumor
  • Clusters surrounded by clear spaces
    • One or only a few clusters per space
    • Scant mucin rarely detectable in spaces
  • Spaces surrounded by loose fibrocollagenous stroma
  • Frequent high nuclear grade reported in some series
  • Frequently has abundant eosinophilic cytoplasm
  • Frequent lymphatic involvement
  • Occasional psammoma bodies
  • Associated DCIS may be of various types
  • Pattern may be predominant or focal
    • No clinical difference between predominant and focal cases
    • No reported cutoff for minimal significant amount of pattern
    • Report such cases as mixed
  • Frequently mixed with infiltrating ductal carcinoma
    • Rarely mixed with other type


  • Incidence
    • Pure about 1%
    • Mixed about 4-7%
  • Frequent local recurrence (70-90%)
  • Poor prognosis
    • Approximate 40% dead of disease in three years
    • Not independent of stage
      • Linked to high incidence of nodal involvement
  • Rare cases reported in males

Grading / Staging / Report

  • Bloom-Scarff-Richardson grading scheme is most widely used
  • Total score and each of the three components should be reported
  • Based on invasive area only
Tubule formationScore
>75% tubules1
10-75% tubules2
<10 span="" tubules="">3

Nuclear pleomorphism (most anaplastic area)Score
Small, regular, uniform nuclei, uniform chromatin1
Moderate varibility in size and shape, vesicular, with visible nucleoli2
Marked variation, vesicular, often with multiple nucleoli3

Mitotic figure count per 10 40x fields (depends on area of field, see key below)Score
0.096 mm20.12 mm20.16 mm20.27 mm20.31 mm2
  • Olympus BX50, BX40 or BH2 or AO or Nikon with 15x eyepiece: 0.096 mm2
  • AO with 10x eyepiece: 0.12 mm2
  • Nikon or Olympus with 10x eyepiece: 0.16 mm2
  • Leitz Ortholux: 0.27 mm2
  • Leitz Diaplan: 0.31 mm2
  • Mitotic count figures based on original data presented for Leitz Ortholux by Elston and Ellis 1991, with modifications based on pubished and measured areas of view
  • Evaluate regions of most active growth, usually in cellular areas at periphery
  • We employ strict criteria for identification of mitotic figures
Sum of above three componentsOverall grade
3-5 pointsGrade I (well differentiated)
6-7 pointsGrade II (moderately differentiated)
8-9 pointsGrade III (poorly differentiated)
  • Micropapillary carcinoma is associated with frequent lymph node metastases
    • Seen even with primary tumors <1 cm="" span="">
    • Seen even with mixed tumors with small micropapillary component
    • Nodal involvement is frequently by micrometastases
  • TNM staging is the most widely used scheme for breast carcinomas but is not universally employed
  • Critical staging criteria for regional lymph nodes
    • Isolated tumor cell clusters
      • Usually identified by immunohistochemistry
        • Term also applies if cells identified by close examination of H&E stain
      • No cluster may be greater than 0.2 mm
      • Multiple such clusters may be present in the same or other nodes
    • Micrometastasis
      • Greater than 0.2 mm, none greater than 2.0 mm
    • Metastasis
      • At least one carcinoma focus over 2.0 mm
        • If one node qualifies as >2.0 mm, count all other nodes even with smaller foci as involved
      • Critical numbers of involved nodes: 1-3, 4-9 and 10 and over
    • Note extranodal extension
  • Excisions: the following are important elements that must be addressed in the report for infiltrative breast carcinomas
    • Grade
      • Total score and individual components
    • Size of neoplasm
      • Give 3 dimensions or greatest dimension
      • Critical cutoffs occur at 0.5 cm and at 2 cm
    • Margins of resection
      • Measure and report the actual distance of both invasive and in situ carcinoma
    • Angiolymphatic invasion
      • Indicate if confined to tumor mass, outside tumor mass or in dermis
    • (Extensive DCIS is not currently felt to be a significant predictor of behavior)
    • Results of special studies performed for diagnosis
    • Results of prognostic special studies performed
      • ER, PR, Proliferation marker, Her2neu
      • If studies were performed on a prior specimen, refer to that report and give results
  • Needle or core biopsies
    • Provisional grade may be given but may defer to excision for definitive grade
    • Presence of absence of angiolymphatic invasion
    • Results of special studies performed for diagnosis
    • Results of prognostic special studies if performed
      • ER, PR, Proliferation marker, Her2neu
      • State if studies are deferred for a later excision specimen
  • Regional lymph nodes
    • Report findings as described above

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Interesting Case

Clinical History:

53 years male,History of hypertension and tachycardia,MRI abdomen:-Left adrenal mass:- size 5.8 cm Right renal mass:- size-3.0cm Microscopic examination of the renal mass showed vascular tumor with diffuse sheets of clear cells having Fuhrman grade III nuclei. There was no evidence of necrosis within the tumor. There was no evidence of extraparenchymal invasion.
Gross examination of the left adrenal gland revealed cortically centered, solid and multinodular mass measuring 6.5 x 6.0 x 5.0 cm and weighing 122 grams. The tumor was encapsulated but showed evidence of extraparenchymal penetration. The tumor had golden brown cut surface with areas of hemorrhage and necrosis. The partial nephrectomy showed 3.0cm x 3.0cm x 3.0 cm yellow solid mass which did not invade into the perinephric adipose tissue.
Microscopically, the adrenal mass had predominant diffuse sheets and focal trabecular arrangements. The former pattern was present in about third of tumor. The cells had clear cytoplasm and round to ovoid nuclei with conspicuous nucleoli. Mitotic rate was 9/50 HPF and included atypical forms. Gross necrosis and capsular invasion were documented microscopically. There was no evidence of lymphovascular invasion. Considering the above mentioned features, a Weiss histopathologic score2 of 7/9 was applied.


The differential diagnosis included Renal Cell Carcinoma (RCC) with contralateral adrenal metastasis, Adrenocortical carcinoma (ACC) with contralateral renal metastasis, synchronous RCC and ACC or synchronous RCC and adrenocortical adenoma. A panel of immunohistochemical stains was performed to sort out the diagnosis. Adrenal tumor demonstrated strong Vimentin positivity and is negative for CK7, CK20, E1/AE3, EMA, Synaptophysin and S100.Renal cell carcinoma was positive for CK7, AE1/AE3, EMA (weak) and Vimentin. It was negative for CK20, Synaptophysin and S100. The difference of immunoprofile between the two tumors documented that they originated from two different primaries.

Final Diagnosis:

The diagnosis of synchronous RCC and ACC rather than metastasis influences the prognosis.


The longest disease free interval after removal of contralateral adrenal metastasis was 12.1 years8 and the longest crude survival was 14.3 years. In contrast non metastazing RCC has an excellent prognosis if no metastasis developed.